bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel insights into Emx2 and Dmrta2 cooperation during cortex development and evidence for Dmrta2 function in choroid plexus
Authors: Anirudhan Jithu , Shen Xueyi , Szemes Tünde , Dieu Marc , Azouz Abdulkader , Conrard Louise , Doumont Gilles , Sitte Maren , Achouri Younes , Kricha Sadia , Salinas-Riester Gabriela , Renard Patricia , Bellefroid Eric J. 
Published: September 2024

ABSTRACTEarly dorsal telencephalon development is coordinated by an interplay of transcription factors that exhibit a graded expression pattern in neural progenitors. How they function together to orchestrate cortical development remains largely unknown. TheEmx2andDmrta2genes encode TFs that are expressed in a similar caudomedialhigh/ rostrolaterallowgradient in the ventricular zone of the developing dorsal telencephalon with, in the medial pallium,Dmrta2but notEmx2expressed in the developing choroid plexus. Their constitutive loss has been shown to impart similar cortical abnormalities, and their combined deletion exacerbates the phenotypes, suggesting possible cooperation during cortex development. In this study, we utilized molecular and genetic approaches to dissect how Emx2 functions with Dmrta2 during cortical development. Our results show that while they regulate a similar set of genes, their common direct targets are limited but include key regulators of cortical development. Identification of the interaction partners of Emx2 suggests that it coordinates with the LIM-domain binding protein Ldb1 to execute the activation and repression of some of its downstream targets. Finally, whileEmx2is known to suppress choroid plexus development, we also provide evidence thatDmrta2is in contrast required for choroid plexus since in its absence in medial telencephalic progenitors, mice develop hydrocephalous postnatally, a phenotype that appears to be due to a compromised cytoarchitecture. Together, these data indicate that Emx2 and Dmrta2 have similar but also distinct functions in telencephalon development and provide the first insights into Emx2 mechanism of action.SIGNIFICANCE STATEMENTEmx2andDmrta2encode transcription factors that generate similar phenotypes upon their loss in the developing cortex suggesting possible cooperation. Here we explored how Emx2 functions with Dmrta2 during cortical development. Results obtained indicate that Emx2 directly regulates with Dmrta2 only a few genes, some coding for key cortical determinants and that Emx2 utilizes the Ldb1 cofactor for the regulation of some of its targets. Results also suggest that, unlike Emx2 which suppresses choroid plexus development, Dmrta2 is required for choroid plexus as its loss in medial telencephalic progenitors leads to hydrocephalus. Together, our results reveal that Emx2 and Dmrta2 have similar but also distinct functions during telencephalon development and provide novel insights into the mechanism of action of Emx2.
Hippocampal γCaMKII dopaminylation promotes synaptic-to-nuclear signaling and memory formation
Authors: Stewart Andrew F. , Fulton Sasha L. , Durand-de Cuttoli Romain , Thompson Robert E. , Chen Peng-Jen , Brindley Elizabeth , Cetin Bulent , Farrelly Lorna A. , Futamura Rita , Claypool Sarah , Bastle Ryan M. , Di Salvo Giuseppina , Peralta Christopher , Molina Henrik , Baljinnyam Erdene , Marro Samuele G. , Russo Scott J. , DeVita Robert J. , Muir Tom W. , Maze Ian 
Published: September 2024

ABSTRACTProtein monoaminylation is a class of posttranslational modification (PTM) that contributes to transcription, physiology and behavior. While recent analyses have focused on histones as critical substrates of monoaminylation, the broader repertoire of monoaminylated proteins in brain remains unclear. Here, we report the development/implementation of a chemical probe for the bioorthogonal labeling, enrichment and proteomics-based detection of dopaminylated proteins in brain. We identified 1,557 dopaminylated proteins – many synaptic – including γCaMKII, which mediates Ca2+-dependent cellular signaling and hippocampal-dependent memory. We found that γCaMKII dopaminylation is largely synaptic and mediates synaptic-to-nuclear signaling, neuronal gene expression and intrinsic excitability, and contextual memory. These results indicate a critical role for synaptic dopaminylation in adaptive brain plasticity, and may suggest roles for these phenomena in pathologies associated with altered monoaminergic signaling.
Spatial Development of Brain Networks During The First Six Postnatal Months
Authors: Seraji Masoud , Shultz Sarah , Li Qiang , Fu Zening , Calhoun Vince D , Iraji Armin 
Published: September 2024

AbstractThe initial months of life constitute a crucial period for human development. A comprehensive understanding of this early phase is essential for unraveling the origins of neurodevelopmental disorders and promoting infant brain health. This study uniquely focuses on the spatial development of intrinsic brain connectivity networks during infancy, which has been less explored compared to functional connectivity. We utilized independent component analysis on resting-state fMRI data from 74 infants to assess how the spatial organization of infant brain networks evolves between birth and six months.Our findings reveal significant changes in spatial characteristics, including an a notable rise in the network-averaged spatial similarity across age, reflecting how closely each participant-specific spatial map aligns with the group-level map for each network. We also observed a marked reduction in the network engagement range by age, representing the extent of voxel intensity range fluctuation within each network. This suggests a continuing process of consolidation, where voxel contributions to the network become more uniform, as indicated by the narrowing of intensity values. The network strength, calculated as the average of all the voxel intensities in the network, indicating the degree of involvement to the specific functional network, increased across age in several networks, such as frontal-mPFC, primary, and secondary visual networks. The network size, along with the network center of mass, illustrating spatial distribution alterations of brain networks by age, varied across different networks. For instance, both metrics increased across age in the secondary visual network but decreased in the temporal network. Additionally, we examined the networks in relation to their linear versus non-linear developmental trajectories across all spatial characteristics, providing a deeper understanding of how these patterns evolve during early infancy. These findings contribute to early brain development understanding and offer insights into potential markers of consolidation and spatial reorganization in large-scale brain networks during infancy.
TBC1D24 regulates mitochondria and endoplasmic reticulum-mitochondria contact sites
Authors: Benhammouda Sara , Rousseau Justine , Campeau Philippe M. , Germain Marc 
Published: September 2024

AbstractThe RabGAP protein TBC1D24 is mutated in several neurological disorders including DOORS syndrome (Deafness, Onycho-Osteodystrophy, Mental Retardation, Seizures). Although TBC1D24 comprises two highly conserved domains — the Tre2/Bub2/Cdc16 (TBC) domain and the TLDc domain — both of which seem to play critical roles in cellular functions, its exact physiological function within the cell remains poorly understood. Here, we show that TBC1D24 affects mitochondrial structure and activity. Specifically, both primary fibroblasts from patients with TBC1D24 mutations and cells in which TBC1D24 has been knocked down exhibit fragmented mitochondria, decreased ATP production, and reduced mitochondrial membrane potential. Importantly, loss or mutation of TBC1D24 also alters sites of contact between the endoplasmic reticulum (ER) and mitochondria (ERMCS). These sites are vital for mitochondrial fusion and fission processes, which regulate mitochondrial dynamics and, consequently, mitochondrial activity. Altogether, our results uncover a new role for TBC1D24 in the regulation of mitochondrial functions and ERMCS which likely contribute to the neurological dysfunction present in affected patients.
Sox9prevents retinal degeneration and is required for limbal stem cell differentiation in the adult mouse eye
Authors: Hurtado Alicia , López-Soriano Víctor , Lao Miguel , Celis-Barroso M. Ángeles , Lazúen Pilar , Chacón de Castro Alejandro , Ramírez-Casas Yolanda , Alaminos Miguel , Collinson J. Martin , Burgos Miguel , Jiménez Rafael , Carmona F. David , Barrionuevo Francisco J. 
Published: September 2024

ABSTRACTSox9is a transcription factor with multiple roles during development and in adult organ homeostasis. In the adult eye,Sox9expression persists in several cell types, including the retinal pigmented epithelium cells and the Müller glial cells, as well as in the limbal and corneal basal epithelia. To uncover the role ofSox9in these cell types, we induced the deletion of the gene in adult mice. We found that, afterSox9ablation, mutant mice undergo a severe process of retinal degeneration characterized by the loss of Müller glial cells and complete depletion of the photoreceptors layer. Moreover, by combining single-cell RNA sequencing andSox9lineage tracing, we found thatSox9is expressed in a basal limbal stem cell population with the ability to form two types of long-lived cell clones involved in stem cell maintenance and homeostasis. Mosaic analysis ofSox9positive and negative cells confirmed that the gene is essential for limbal stem cell differentiation. Our results show thatSox9is required for the maintenance of retinal integrity and for limbal stem cell differentiation in the adult mouse eye.
Social Isolation Intensifiesadgrl3.1-Related Externalizing and Internalizing Behaviors in Zebrafish
Authors: Fontana Barbara D. , Alnassar Nancy , Norton William H.J. , Parker Matthew O. 
Published: September 2024

AbstractExternalizing disorders (EDs) are characterized by outward-directed behaviors such as aggression and hyperactivity. They are influenced by gene-environment interactions, yet our understanding of the genetic predispositions and environmental contexts that give rise to them is incomplete. Additionally, people with EDs often exhibit comorbid internalizing symptoms, which can complicate the clinical presentation and treatment strategies. Following on from our previous studies, we examined genes x environment interaction as a risk factor for EDs by looking at internalizing and externalizing behaviors after social isolation. Specifically, we subjectedadgrl3.1knockout zebrafish — characterized by hyperactivity and impulsivity — to a 2-week social isolation protocol. We subsequently assessed the impact on anxiety-like behavior, abnormal repetitive behaviors, working memory, and social interactions. Genotype-specific additive effects emerged, with socially isolatedadgrl3.1knockout fish exhibiting intensified comorbid phenotypes, including increased anxiety, abnormal repetitive behaviors, reduced working memory, and altered shoaling, when compared to WT fish. The findings demonstrate that genetic predispositions interact with environmental stressors, such as social isolation, to exacerbate both externalizing and internalizing symptoms. This underlines the necessity for comprehensive diagnostic and intervention strategies.
Dynamic metal coordination controls chemoselectivity in radical halogenases
Authors: Kissman Elijah N. , Kipouros Ioannis , Slater Jeffrey W. , Stone Elizabeth A. , Yang Avery Y. , Braun Augustin , Ensberg Alder R. , Whitten Andrew M. , Chatterjee Kuntal , Bogacz Isabel , Yano Junko , Bollinger J. Martin , Chang Michelle C.Y. 
Published: September 2024

AbstractThe activation of inert C(sp3)-H bonds by non-heme Fe enzymes plays a key role in metabolism, epigenetics, and signaling, while providing a powerful biocatalytic platform for the chemical synthesis of molecules with increasedsp3complexity. In this context, FeII/α-ketoglutarate-dependent radical halogenases represent a broadly interesting system, as they are uniquely capable of carrying out transfer of a diverse array of bound anions following C-H activation. Here, we provide the first experimental evidence that bifurcation of H-atom abstraction and radical rebound is driven both by the ability of a dynamic metal coordination sphere to reorganize as well as by a second-sphere hydrogen-bond network where only two residues (Asn224 and Ile151) are necessary and sufficient. The identification of this minimal motif provides a paradigm for understanding the evolution of catalytic plasticity in these enzymes and yields new insight into the design principles by which to expand their reaction scope.
Viral fragments in the urine proteome: New clues to the cause of fever
Authors: Yang Minhui , Zhao Chenyang , Gao Youhe 
Published: September 2024

Abstract[Background]Fever of unknown origin refers to a medical condition where the cause of the fever is not yet clear. This condition is common in various potential diseases and usually requires detailed examination and testing to determine the specific cause. No one has ever looked for the cause of fever in urine proteomics, and this study provides clues and diagnostic evidence for patients with fever of unknown origin through urine proteomics analysis.[Methods]We attempted virus-wide database searching for the first time in urine samples, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze urine proteins from febrile patients. Virus protein fragments were identified and retrieved.[Results]In urine samples, we detected specific peptide segments from various viruses including monkeypox virus, saliva virus A, human herpesvirus 8 type P, Middle East respiratory syndrome-related coronavirus, rotavirus A, foot-and-mouth disease virus (strain NZ2), human herpesvirus 2 (strain HG52), human adenovirus E serotype 4, influenza A virus, human coronavirus NL63, influenza B virus (strain W3), Nipah virus, and hepatitis C virus genotype 2k (isolate VAT96), among others. Several viruses showed significantly higher detection levels in febrile patients compared to controls, with saliva virus A showing an increase by over 4200-fold, and multiple virus proteins increased by more than 20-fold. It is noteworthy that the overall protein retrieval error rate was less than 1%, and the individual protein retrieval error rate for each sample was less than 5%, ensuring highly reliable protein retrieval results with a probability of error across all proteins of only 1.2×e-17.[Conclusion]Reliable virus protein fragments can be retrieved from urine proteomics, providing clues for febrile patient investigation and potentially applicable to the exploration of any unknown diseases. By adopting our method, there is no need to know in advance what specific viruses are contained in the sample, as long as the information of these viruses has been stored in the virus database, comprehensive and extensive virus retrieval can be achieved. This method significantly expands the coverage of virus detection and improves the flexibility and efficiency of detection.
A Method for Visual Psychophysics based on the Navigational Behaviour of Desert Ants (Melophorus bagoti)
Authors: Deeti Sudhakar , Lionetti Vito , Cheng Ken 
Published: September 2024

ABSTRACTThe Australian desert antMelophorus bagotiis known to navigate in their complex visual environment relying on path integration and landmark learning. We investigated the navigational behaviour of desert ants in response to visual stimulus changes along their route to a food source. Ants were trained to self-navigate a track between their nest and a feeder, with visual stimuli introduced near the feeder. After three days of training, we altered the visual scene by changing colours and observed the ants’ reactions. The results showed that ants in the test conditions, when visual changes were introduced, displayed more meandering paths, increased scanning behaviour, and slower speeds compared to control conditions. The sinuosity of their paths increased, and their orientation became less efficient. Additionally, changes in colour led to significant alterations in path characteristics, including a higher frequency of head oscillations and deviations from straight-line paths. These findings suggest that disruption to visual cues used for navigation causes noticeable changes in their movement patterns. A subset of these changes, easy to measure and calculate, can provide a signature to indicate that ants have detected a change in the visual stimuli. This proof-of-concept study thus highlights a method for studying visual psychophysics in ants in their natural habitat.
Mammalian Retinal Bipolar Cells: Morphological Identification and Systematic Classification in Rabbit Retina with a Comparative Perspective
Authors: Famiglietti Edward V. 
Published: September 2024

AbstractRetinal bipolar cells (BCs) convey visual signals from photoreceptors to more than 50 types of rabbit retinal ganglion cells (Famiglietti, 2020). More than 40 years ago, 10-11 types of bipolar cell were recognized in rabbit and cat retinas (Famiglietti, 1981). Twenty years later 10 were identified in mouse, rat, and monkey, while recent molecular genetic studies indicate that there are 15 types of bipolar cell in mouse retina (Shekhar et al., 2016). The present detailed study of more than 800 bipolar cells in ten Golgi-impregnated rabbit retinas indicates that there are 14-16 types of cone bipolar cell and one type of rod bipolar cell in rabbit retina. These have been carefully analyzed in terms of dendritic and axonal morphology, and axon terminal stratification with respect to fiducial starburst amacrine cells. In fortuitous proximity, several types of bipolar cell can be related to identified ganglion cells by stratification and by contacts suggestive of synaptic connection. These results are compared with other studies of rabbit bipolar cells. Homologies with bipolar cells of mouse and monkey are considered in functional terms.
Filamentation and proline inhibition of glutamate kinase
Authors: Zhang Tianyi , Leng Qingqing , Hu Huan-Huan , Liu Ji-Long 
Published: September 2024

AbstractGlutamate kinase (GK) is the first committed enzyme in the proline biosynthesis pathway. Belonging to amino acid kinase (AAK) superfamily, most prokaryotic GKs have an additional PseudoUridine synthase and Archaeosine transglycosylase (PUA) domain at the C-terminus, while the function of the PUA domain in GK is poorly understood. Here, we find thatEscherichia coliGK (EcGK) assembles into filaments and bundles in the state of apo and proline binding. Using cryogenic electron microscopy, we determine the high-resolution structures of EcGK filaments and bundles. The PUA domain is necessary for EcGK filaments and bundles, and the main interfaces have been clearly defined. The feedback inhibitor proline binds at the same pocket as substrate glutamate, inducing conformational changes on nearby regulatory loop which facilitate proline binding. The PUA domain stabilizes the regulatory loop and contributes to proline feedback inhibition. This study reports the special filament-based assembly of EcGK at apo and proline binding state. The first proline binding structure in the GK family illustrates the feedback inhibition mechanism. Intriguingly, the PUA domain is involved in both filamentation and feedback inhibition of EcGK, revealing the versatility of this ancient domain.
Preventing Inappropriate Signals Pre- and Post-Ligand Perception by a Toggle-Switch Mechanism of ERECTA
Authors: Chen Liangliang , Maes Michal , Cochran Alicia M. , Avila Julian R. , Derbyshire Paul , Sklenar Jan , Haas Kelsey M. , Villén Judit , Menke Frank L.H. , Torii Keiko U. 
Published: September 2024

AbstractDynamic control of signaling events requires swift regulation of receptors at an active state. By focusing on Arabidopsis ERECTA (ER) receptor kinase, which perceives peptide ligands to control multiple developmental processes, we report a mechanism preventing inappropriate receptor activity. The ER C-terminal tail (ER_CT) functions as an autoinhibitory domain: its removal confers higher kinase activity and hyperactivity during inflorescence and stomatal development. ER_CT is required for the binding of a receptor kinase inhibitor, BKI1, and two U-box E3 ligases PUB30 and PUB31 that inactivate activated ER. We further identify ER_CT as a phosphodomain trans-phosphorylated by the co-receptor BAK1. The phosphorylation impacts the tail structure, likely releasing from autoinhibition. The phosphonull version enhances BKI1 association, whereas the phosphomimetic version promotes PUB30/31 association. Thus, ER_CT acts as an off-on-off toggle switch, facilitating the release of BKI1 inhibition, enabling signal activation, and swiftly turning over the receptors afterwards. Our results elucidate a mechanism fine-tuning receptor signaling via a phosphoswitch module, keeping the receptor at a low basal state and ensuring the robust yet transient activation upon ligand perception.SignificanceCells perceive and process external signals through their cell-surface receptors, whose activity must be tightly maintained to prevent the spread of misinformation. How do plant cells prevent the inappropriate receptor activity? We identify a structural module within the C-terminal tail of the ERECTA (ER_CT), that inhibits the receptor pre- and post-signal activation. The ER_CT comprises of a linker and an α-helix. Before activation, ER_CT is autoinhibitory and associates with an inhibitory protein. Ligand perception triggers the transphosphorylation of ER_CT by the co-receptor, which then recruits a degradation machinery to swiftly turn over the activated receptor. Thus, we reveal an off-on-off toggle switch mechanism that finely adjusts the activity of the plant receptor, enabling the precise control over cell signaling.
Probing The Edge Of Synchronization: Cortical Activity Transiently Slips Into Slow Waves In Behaving Monkeys
Authors: Pazienti Antonio , Galluzzi Andrea , Pani Pierpaolo , Ferraina Stefano , Mattia Maurizio 
Published: September 2024

AbstractBrain networks oscillate between sleep and wakefulness, following circadian rhythms. Theoretical models suggest distinct phases within this cycle, separated by a critical point where long-range activity patterns emerge, an advantageous condition for information processing in cortical networks. However, the exact nature of this critical dynamics remains elusive. A key question is whether the brain operates at this critical point during cognitive tasks or only during resting wakefulness. Here, we analyzed neural signals from the premotor cortex (PMC) of two macaque monkeys engaged in a delayed-reaching task and under drug-induced unconsciousness. We found evidence of criticality during resting periods at the end of behavioral trials in the awake state. This scale-free activity appeared as coordinated traveling waves, like those observed during anesthesia. As predicted by spiking networks models, activity-dependent adaptation influences wave size, supporting the hypothesis that the PMC operates near a synchronization phase transition while avoiding it during active behaviors.