bluuebunny/crossref_metadata_2025 huggingface dataset:
Attenuated processing of vowels in the left hemisphere predicts speech-in-noise perception deficit in children with autism
Authors: Fadeev Kirill A. , Romero Reyes Ilacai V. , Goiaeva Dzerassa E. , Obukhova Tatiana S. , Ovsiannikova Tatiana M. , Prokofyev Andrey O. , Rytikova Anna M. , Novikov Artem Y. , Kozunov Vladimir V. , Stroganova Tatiana A. , Orekhova Elena V.
Published: June 2024

Background

Difficulties with speech-in-noise perception in autism spectrum disorders (ASD) may be associated with impaired analysis of speech sounds, such as vowels, which represent the fundamental phoneme constituents of human speech. Vowels elicit early (< 100 ms) sustained processing negativity (SPN) in the auditory cortex that reflects the detection of an acoustic pattern based on the presence of formant structure and/or periodic envelope information (f0) and its transformation into an auditory “object”.

Methods

We used magnetoencephalography (MEG) and individual brain models to investigate whether SPN is altered in children with ASD and whether this deficit is associated with impairment in their ability to perceive speech in the background of noise. MEG was recorded while boys with ASD and typically developing boys passively listened to sounds that differed in the presence/absence off0periodicity and formant structure. Word-in-noise perception was assessed in the separate psychoacoustic experiment using stationary and amplitude modulated noise with varying signal-to-noise ratio.

Results

SPN was present in both groups with similarly early onset. In children with ASD, SPN associated with processing formant structure was reduced predominantly in the cortical areas lateral to and medial to the primary auditory cortex, starting at ∼ 150 - 200 ms after the stimulus onset. In the left hemisphere, this deficit correlated with impaired ability of children with ASD to recognize words in amplitude-modulated noise, but not in stationary noise

Conclusions

These results suggest that perceptual grouping of vowel formants into phonemes is impaired in children with ASD and that, in the left hemisphere, this deficit contributes to their difficulties with speech perception in fluctuating background noise.
CD-GPT As a Biological Foundation Model Bridging the Gap between Molecular Sequences Through Central Dogma
Authors: Zhu Xiao , Qin Chenchen , Wang Fang , Yang Fan , He Bing , Zhao Yu , Yao Jianhua
Published: June 2024

The central dogma serves as a fundamental framework for understanding the flow and expression of genetic information within living organisms, facilitating the connection of diverse biological sequences across molecule types. In this study, we present CD-GPT (Central Dogma Generative Pretrained Transformer), a generative biological foundation model with 1 billion parameters, aiming to capture the sequence relationships between DNA, RNA, and proteins. We model sequences in a unified representational space and employ a shared, multi-molecule vocabulary to narrow their distances in the embedding space effectively. Through extensive pretraining on nucleotide and amino acid sequence data, CD-GPT exhibits exceptional performance in a wide range of predictive and generative downstream tasks, including mono-molecular and multi-molecular analyses. Notably, CD-GPT excels in tasks such as genomic element detection, protein property prediction, RNA-protein interaction identification and also generative tasks like protein generation and reverse translation. The versatility of CD-GPT opens up promising avenues for advanced multi-omics analysis.
BioMapAI: Artificial Intelligence Multi-Omics Modeling of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
Authors: Xiong Ruoyun , Aiken Elizabeth , Caldwell Ryan , Vernon Suzanne D. , Kozhaya Lina , Gunter Courtney , Bateman Lucinda , Unutmaz Derya , Oh Julia
Published: June 2024

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic illness with a multifactorial etiology and heterogeneous symptomatology, posing major challenges for diagnosis and treatment. Here, we present BioMapAI, a supervised deep neural network trained on a four-year, longitudinal, multi-omics dataset from 249 participants, which integrates gut metagenomics, plasma metabolomics, immune cell profiling, blood laboratory data, and detailed clinical symptoms. By simultaneously modeling these diverse data types to predict clinical severity, BioMapAI identifies disease- and symptom-specific biomarkers and robustly classifies ME/CFS in both held-out and independent external cohorts. Using an explainable AI approach, we construct the first connectivity map spanning the microbiome, immune system, and plasma metabolome in health and ME/CFS, adjusted for age, gender, and additional clinical factors. This map uncovers disrupted associations between microbial metabolism (e.g., short-chain fatty acids, branched-chain amino acids, tryptophan, benzoate), plasma lipids and bile acids, and heightened inflammatory responses in mucosal and inflammatory T cell subsets (MAIT, γδT) secreting IFNγ and GzA. Overall, BioMapAI provides unprecedented systems-level insights into ME/CFS, refining existing hypotheses and hypothesizing new pathways associated to the disease’s heterogeneous symptoms.
Unbiased and comprehensive identification of viral encoded circular RNAs in a large range of viral species and families
Authors: Chasseur Alexis S , Bellefroid Maxime , Galais Mathilde , Gong Meijiao , Mathieu Sarah , Ponsard Camille , Vreux Laure , Yague-Sanz Carlo , Dewals Benjamin G , Gillet Nicolas A , Muylkens Benoît , Van Lint Carine , Coupeau Damien
Published: June 2024

Non-coding RNAs play a significant role in viral infection cycles, with recent attention focused on circular RNAs (circRNAs) originating from various viral families. Notably, these circRNAs have been associated with oncogenesis and alterations in viral fitness. However, identifying their expression has proven more challenging than initially anticipated due to unique viral characteristics. This challenge has the potential to impede progress in our understanding of viral circRNAs. Key hurdles in working with viral genomes include: (1) the presence of repetitive regions that can lead to misalignment of sequencing reads, and (2) unconventional splicing mechanisms that deviate from conserved eukaryotic patterns.

To address these challenges, we developed vCircTrappist, a bioinformatic pipeline tailored to identify backsplicing events and pinpoint loci expressing circRNAs in RNA sequencing data. Applying this pipeline, we obtained novel insights from both new and existing datasets encompassing a range of animal and human pathogens belonging to Herpesviridae, Retroviridae, Adenoviridae and Orthomyxoviridae families. Subsequent RT-PCR and Sanger sequencings validated the accuracy of the developed bioinformatic tool for a selection of new candidate viral encoded circRNAs. These findings demonstrate that vCircTrappist is an open and unbiased approach for comprehensive identification of virus-derived circRNAs.

Significance Statement

Circular RNAs (circRNAs) were revealed to have prominent roles in cellular life in the past decade. They were more recently shown to be expressed by viruses, influencing their infectious cycles and host-pathogen relationship. In this context, viruses that were not previously associated with cellular splicing processes are shown to express circRNAs through unknown mechanisms. These non-canonical circRNAs were already shown to be important in the viral cycle and pathogenesis of the viruses they are encoded from. Here, we propose a bioinformatics pipeline that bypasses the limitations of the existing tools in the identification of viral circRNA. Using this pipeline, we discovered numerous candidates and invite the reader to start its own exploration in the realm of viral encoded circRNAs.

Graphical Abstract
Deployment of tethered gene drive for confined suppression in continuous space requires avoiding drive wave interference
Authors: Feng Ruobing , Champer Jackson
Published: June 2024

Gene drives have great potential for suppression of pest populations and removal of exotic invasive species. CRISPR homing suppression drive is a powerful but unconfined drive, posing risks of uncontrolled spread. Thus, developing methods for confining a gene drive is of great significance. Tethered drive combines a confined system such as Toxin-Antidote Recessive Embryo (TARE) drive with a strong drive such as a homing suppression drive. It can prevent the homing drive from spreading beyond the confined drive and can be constructed readily, giving it good prospects for future development. However, we have found that care must be taken when deploying tethered drive systems in some scenarios. Simulations of tethered drive in a panmictic population model reveal that successful deployment requires a proper release ratio between the two components, tailored to prevent the suppression drive from eliminating the confined system before it has the chance to spread. Spatial models where the population moves over a one-dimensional landscape display a more serious phenomenon of drive wave interference between the two tethered drive components. If the faster suppression drive wave catches up to the confined drive wave, success is still possible, but it is dependent on drive performance and ecological parameters. Two-dimensional simulations further restrict the parameter range for drive success. Thus, careful consideration must be given to drive performance and ecological conditions, as well as specific release proposals for potential application of tethered drive systems.
Distinct visual processing networks for foveal and peripheral visual fields
Authors: Zhang Jie , Zhou Huihui , Wang Shuo
Published: June 2024

Foveal and peripheral vision are two distinct modes of visual processing essential for navigating the world. However, it remains unclear if they engage different neural mechanisms and circuits within the visual attentional system. Here, we trained macaques to perform a free-gaze visual search task using natural face and object stimuli and recorded a large number of 14588 visually responsive neurons from a broadly distributed network of brain regions involved in visual attentional processing. Foveal and peripheral units had substantially different proportions across brain regions and exhibited systematic differences in encoding visual information and visual attention. The spike-LFP coherence of foveal units was more extensively modulated by both attention and visual selectivity, thus indicating differential engagement of the attention and visual coding network compared to peripheral units. Furthermore, we delineated the interaction and coordination between foveal and peripheral processing for spatial attention and saccade selection. Finally, the search became more efficient with increasing target-induced desynchronization, and foveal and peripheral units exhibited different correlations between neural responses and search behavior. Together, the systematic differences between foveal and peripheral processing provide valuable insights into how the brain processes and integrates visual information from different regions of the visual field.

Significance Statement

This study investigates the systematic differences between foveal and peripheral vision, two crucial components of visual processing essential for navigating our surroundings. By simultaneously recording from a large number of neurons in the visual attentional neural network, we revealed substantial variations in the proportion and functional characteristics of foveal and peripheral units across different brain regions. We uncovered differential modulation of functional connectivity by attention and visual selectivity, elucidated the intricate interplay between foveal and peripheral processing in spatial attention and saccade selection, and linked neural responses to search behavior. Overall, our study contributes to a deeper understanding of how the brain processes and integrates visual information for active visual behaviors.
Propagating cortical waves coordinate sensory encoding and memory retrieval in the human brain
Authors: Yang Yifan , Leopold David , Duyn Jeff , Liu Xiao
Published: June 2024

Complex behavior entails a balance between taking in sensory information from the environment and utilizing previously learned internal information. Experiments in behaving mice have demonstrated that the brain continually alternates between outward and inward modes of cognition, switching its mode of operation every few seconds. Further, each state transition is marked by a stereotyped cascade of neuronal spiking that pervades most forebrain structures. Here we analyzed large fMRI datasets to demonstrate that a similar switching mechanism governs the operation of the human brain. We found that human brain activity was punctuated every several seconds by coherent, propagating waves emerging in the exteroceptive sensorimotor regions and terminating in the interoceptive default mode network. As in the mouse, the issuance of such events coincided with fluctuations in pupil size, indicating a tight relationship with arousal fluctuations, and this phenomenon occurred across behavioral states. Strikingly, concurrent measurement of human performance in a visual memory task indicated that each cycle of propagating fMRI waves sequentially promoted the encoding of semantic information and self-directed retrieval of memories. Together, these findings indicate that human cognitive performance is governed by autonomous switching between exteroceptive and interoceptive states. This apparently conserved feature of mammalian brain physiology bears directly on the integration of sensory and mnemonic information during everyday behavior.
Comprehensive evaluation of lifespan-extending molecules inC. elegans
Authors: Phelps Grace B. , Morin Jonas , Pinto Carla , Schoenfeldt Lucas , Guilmot Sebastien , Ocampo Alejandro , Perez Kevin
Published: June 2024

The nematodeC. eleganshas long served as a gold-standard model organism in aging research, particularly since the discovery of long-lived mutants in conserved aging pathways including daf-2 (IGF1) and age-1 (PI3K). Its short lifespan and small size make it highly suitable for high throughput experiments. While numerous molecules have been tested for their effects onC. eleganslifespan, consensus is still lacking regarding the most effective and reproducible compounds. Confounding effects, especially those related to drug-bacteria interactions, remain a contentious issue in the literature. In this study, we evaluated 16 of the most frequently reported lifespan-extending molecules inC. elegans, examining their effects on lifespan with two different diets (live and UV-killed OP50). In addition, we assessed the compounds’ impact on bacterial growth, their effects on various nematode strains, and the impact of the starting age of treatment. Our findings first confirmed robust lifespan extension with many, but not all, of the 16 tested compounds from the literature, and revealed that some of them could be combined to get synergistic effects. Additionally, we showed that some of these compounds also extend lifespan in the flyD. melanogaster,demonstrating a conserved effect across species. Finally, by expanding our screen to a broader pool of molecules, we identified novel lifespan-extending compounds inC. elegans.
Positionally distinct interferon stimulated dermal immune acting fibroblasts promote neutrophil recruitment in Sweet’s syndrome
Authors: Cavagnero Kellen J. , Albright Julie , Li Fengwu , Dokoshi Tatsuya , Bogle Rachael , Kirma Joseph , Kahlenberg J. Michelle , Billi Allison C. , Fox Jennifer , Coon Anthony , Dobry Craig J. , Hinds Brian , Tsoi Lam C. , Harms Paul W. , Gudjonsson Johann E. , Gallo Richard L.
Published: June 2024

Sweet’s syndrome is a poorly understood inflammatory skin disease characterized by neutrophil infiltration to the dermis. Single-nucleus and bulk transcriptomics of archival clinical samples of Sweet’s syndrome revealed a prominent interferon signature in Sweet’s syndrome skin that was reduced in tissue from other neutrophilic dermatoses. This signature was observed in different subsets of cells, including fibroblasts that expressed interferon-induced genes. Functionally, this response was supported by analysis of cultured primary human dermal fibroblasts that were observed to highly express neutrophil chemokines in response to activation by type I interferon. Furthermore, single-molecule resolution spatial transcriptomics of skin in Sweet’s syndrome identified positionally distinct immune acting fibroblasts that included a CXCL1+ subset proximal to neutrophils and a CXCL12+ subset distal to the neutrophilic infiltrate. This study defines the cellular landscape of neutrophilic dermatoses and suggests dermal immune acting fibroblasts play a role in the pathogenesis of Sweet’s syndrome through recognition of type I interferons.
Impact of dendritic non-linearities on the computational capabilities of neurons
Authors: Lauditi Clarissa , Malatesta Enrico M. , Pittorino Fabrizio , Baldassi Carlo , Brunel Nicolas , Zecchina Riccardo
Published: June 2024

Multiple neurophysiological experiments have shown that dendritic non-linearities can have a strong influence on synaptic input integration. In this work we model a single neuron as a two-layer computational unit with non-overlapping sign-constrained synaptic weights and a biologically plausible form of dendritic non-linearity, which is analytically tractable using statistical physics methods. Using both analytical and numerical tools, we demonstrate several key computational advantages of non-linear dendritic integration with respect to models with linear synaptic integration. We find that the dendritic non-linearity concurrently enhances the number of possible learned input-output associations and the learning velocity, and we characterize how capacity and learning speed depend on the implemented non-linearity and the levels of dendritic and somatic inhibition. We find that experimentally observed connection probabilities naturally emerge in neurons with sign-constrained synapses as a consequence of non-linear dendritic integration, while in models with linear integration, an additional robustness parameter must be introduced in order to reproduce realistic connection probabilities. Non-linearly induced sparsity comes with a second central advantage for neuronal information processing, i.e. input and synaptic noise robustness. By testing our model on standard real-world benchmark datasets inspired by deep learning practice, we observe empirically that the non-linearity provides an enhancement in generalization performance, showing that it enables to capture more complex input/output relations.
Translational control in the spinal cord regulates gene expression and pain hypersensitivity in the chronic phase of neuropathic pain
Authors: Lister Kevin C. , Wong Calvin , Uttam Sonali , Parisien Marc , Stecum Patricia , Brown Nicole , Cai Weihua , Hooshmandi Mehdi , Gu Ning , Amiri Mehdi , Beaudry Francis , Jafarnejad Seyed Mehdi , Tavares-Ferreira Diana , Inturi Nikhil Nageshwar , Mazhar Khadijah , Zhao Hien T. , Fitzsimmons Bethany , Gkogkas Christos G. , Sonenberg Nahum , Price Theodore J. , Diatchenko Luda , Atlasi Yaser , Mogil Jeffrey S. , Khoutorsky Arkady
Published: June 2024

Sensitization of spinal nociceptive circuits plays a crucial role in neuropathic pain. This sensitization depends on new gene expression that is primarily regulated via transcriptional and translational control mechanisms. The relative roles of these mechanisms in regulating gene expression in the clinically relevant chronic phase of neuropathic pain are not well understood. Here, we show that changes in gene expression in the spinal cord during the chronic phase of neuropathic pain are substantially regulated at the translational level. Downregulating spinal translation at the chronic phase alleviated pain hypersensitivity. Cell-type-specific profiling revealed that spinal inhibitory neurons exhibited greater changes in translation after peripheral nerve injury compared to excitatory neurons. Notably, increasing translation selectively in all inhibitory neurons or parvalbumin-positive (PV+) interneurons, but not excitatory neurons, promoted mechanical pain hypersensitivity. Furthermore, increasing translation in PV+neurons decreased their intrinsic excitability and spiking activity, whereas reducing translation in spinal PV+neurons prevented the nerve injury-induced decrease in excitability. Thus, translational control mechanisms in the spinal cord, particularly in inhibitory neurons, play a role in mediating neuropathic pain hypersensitivity.
Lipidic and senescent macrophages predict progression and response to combinatorial immunotherapy in triple-negative breast cancer
Authors: Chan Chun Lai , To Alex , Zhang Shihui , Wong Jason Wing Hon , Huang Yuanhua , Chao Yiming , Sugimura Ryohichi
Published: June 2024

Immune cell subsets in the tumor predict prognosis. Identifying reliable subsets consistently in multiple patients is clinically important. What’s more advantageous to the field is if such subsets can be a target of immunotherapy. Here we analyzed single-cell RNA-sequencing datasets of patients with triple-negative breast cancer and identified APOE or FABP5-expressing macrophages correlated with poor prognosis. Further validation with TCGA-BRCA cohort detailed molecular signatures of these macrophages as lipidic and senescent. Our receptor-ligand mapping identified lipidic and senescent macrophages both suppress T-lymphoid and myeloid immunogenicity. Finally, we discovered that immune checkpoint therapy combined with chemotherapy reprogrammed anti-tumor microenvironment enriched with FOLR2+macrophages facilitated T-cell activations. This suggests that lipidic and senescent macrophages could be a therapeutic target of immune checkpoint therapy.
AB-free kava enhances resilience against the adverse health effects of tobacco smoke in mice
Authors: Bian Tengfei , Lynch Allison , Ballas Kayleigh , Mamallapalli Jessica , Freeman Breanne , Scala Alexander , Wang Yifan , Trabouls Hussein , Chellian Ranjith kumar , Fagan Amy , Tang Zhixin , Ding Haocheng , De Umasankar , Fredenburg Kristianna M. , Huo Zhiguang , Baglole Carolyn J. , Zhang Weizhou , Reznikov Leah R. , Bruijnzeel Adriaan W. , Xing Chengguo
Published: June 2024

Tobacco smoke remains a serious global issue, resulting in serious health complications, contributing to the onsets of numerous preventive diseases, and imposing significant financial burdens. Despite regulatory policies and cessation measures aimed at curbing its usage, novel interventions are urgently needed for effective damage reduction. Our preclinical and pilot clinical studies showed that AB-free kava has the potential to reduce tobacco smoke-induced lung cancer risk, mitigate tobacco dependence, and reduce tobacco use. To understand the scope of its benefits in damage reduction and potential limitations, this study evaluated the effects of AB-free kava on a panel of health indicators in mice exposed to 2 – 4 weeks of daily tobacco smoke exposure. Our comprehensive assessments included global transcriptional profiling of the lung and liver tissues, analysis of lung inflammation, evaluation of lung function, exploration of tobacco nicotine withdrawal, and characterization of the causal PKA signaling pathway. As expected, Tobacco smoke exposure perturbed a wide range of biological processes and compromised multiple functions in mice. Remarkably, AB-free kava demonstrated the ability to globally mitigate tobacco smoke-induced deficits at the molecular and functional levels with promising safety profiles, offering a unique promise to mitigate tobacco smoke-related health damages. Further pre-clinical evaluation and clinical translation are warranted to fully harness the potential of AB-free kava in combating tobacco smoke-related harms.

Graphical Abstract
Methionine Restriction Reduces Lung Cancer Progression and Increases Chemotherapy Response
Authors: Naughton Kassandra J. , Song Xiulong , Childress Avery R. , Skaggs Erika M. , Byrd Aria L. , Gosser Christian M. , Esoe Dave-Preston , DuCote Tanner J. , Plaugher Daniel R. , Lukyanchuk Alexsandr , Goettl Ryan A. , Liu Jinpeng , Brainson Christine F.
Published: June 2024

Targeting tumor metabolism through dietary interventions is an area of growing interest, and may help to improve the significant mortality of aggressive cancers, including non-small cell lung cancer (NSCLC). Here we show that the restriction of methionine in the aggressive KRAS/Lkb1-mutant NSCLC autochthonous mouse model drives decreased tumor progression and increased carboplatin treatment efficacy. Importantly, methionine restriction during early stages of tumorigenesis prevents the lineage switching known to occur in the model, and alters the tumor immune microenvironment (TIME) to have fewer tumor-infiltrating neutrophils. Mechanistically, mutations inLKB1are linked to anti-oxidant production through changes to cystathionine-β-synthase (CBS) expression. Human cell lines with rescuedLKB1show increased CBS levels and resistance to carboplatin, which can be partially rescued by methionine restriction. Furthermore, LKB1 rescued cells, but not mutant cells, show less G2- M arrest and apoptosis in high methionine conditions. Knock-down of CBS sensitized both LKB1 mutant and non-mutated lines to carboplatin, again rescuing the carboplatin resistance of the LKB1 rescued lines. Given that immunotherapy is commonly combined with chemotherapy for NSCLC, we next wanted to understand if T cells are impaired by MR. Therefore, we examined the ability of T cells from MR and control tumor bearing mice to proliferate in culture and found that T cells from MR treated mice had no defects in proliferation, even though we continued the MR conditionsex vivo. We also identified that CBS is most highly correlated with smoking, adenocarcinomas with alveolar and bronchiolar features, and adenosquamous cell carcinomas, implicating its roles in oxidative stress response and lineage fate in human tumors. Taken together, we have shown the importance of MR as a dietary intervention to slow tumor growth and improve treatment outcomes for NSCLC.
Loss of AMPK potentiates inflammation by activating the inflammasome after traumatic brain injury in mice
Authors: Ahmed Mohammad Ejaz , Suhail Hamid , Nematullah Mohammad , Hoda Md Nasrul , Giri Shailendra , Ahmad Abdullah Shafique
Published: June 2024

Traumatic brain injury (TBI) is a significant public health concern characterized by a complex cascade of cellular events. TBI induces adenosine monophosphate-activated protein kinase (AMPK) dysfunction impairs energy balance activates inflammatory cytokines and leads to neuronal damage. AMPK is a key regulator of cellular energy homeostasis during inflammatory responses. Recent research has revealed its key role in modulating the inflammatory process in TBI. Following TBI the activation of AMPK can influence various important pathways and mechanisms including metabolic pathways and inflammatory signaling. Our study investigated the effects of post-TBI loss of AMPK function on functional outcomes inflammasome activation, and inflammatory cytokine production. Male C57BL/6 adult wild-type (WT) and AMPK knockout (AMPK-KO) mice were subjected to a controlled cortical impact (CCI) model of TBI or sham surgery. The mice were tested for behavioral impairment at 24 h post-TBI thereafter, mice were anesthetized, and their brains were quickly removed for histological and biochemical evaluation.In vitrowe investigated inflammasome activation in mixed glial cells stimulated with lipopolysaccharides+ Interferon-gamma (LI) (0.1 µg/20 ng/ml LPS/IFNg) for 6 h to induce an inflammatory response. Estimating the nucleotide-binding domain, leucine-rich–containing family pyrin domain containing western blotting ELISA and qRT-PCR performed 3 (NLRP3) inflammasome activation and cytokine production. Our findings suggest that TBI leads to reduced AMPK phosphorylation in WT mice and that the loss of AMPK correlates with worsened behavioral deficits at 24 h post-TBI in AMPK-KO mice as compared to WT mice. Moreover compared with the WT mice AMPK-KO mice exhibit exacerbated NLRP3 inflammasome activation and increased expression of proinflammatory mediators such as IL-1b IL-6 TNF-a iNOS and Cox 2. These results align with thein vitrostudies using brain glial cells under inflammatory conditions, demonstrating greater activation of inflammasome components in AMPK-KO mice than in WT mice. Our results highlighted the critical role of AMPK in TBI outcomes. We found that the absence of AMPK worsens behavioral deficits and heightens inflammasome-mediated inflammation thereby exacerbating brain injury after TBI. Restoring AMPK activity after TBI could be a promising therapeutic approach for alleviating TBI-related damage.
Stereotyped spatiotemporal dynamics of spontaneous activity in visual cortex prior to eye-opening
Authors: Kettlewell Luna , Sederberg Audrey , Smith Gordon B.
Published: June 2024

Over the course of development, functional sensory representations emerge in the visual cortex. Prior to eye-opening, modular patterns of spontaneous activity form long-range networks that may serve as a precursor for mature network organization. Although the spatial structure of these networks has been well studied, their temporal features, which may contribute to their continued plasticity and development, remain largely uncharacterized. To address this, we imaged hours of spontaneous network activity in the visual cortex of developing ferrets of both sexes utilizing a fast calcium indicator (GCaMP8m) and widefield imaging at high temporal resolution (50Hz), then segmented out spatiotemporal events. The spatial structure of this activity was highly modular, exhibiting spatially segregated active domains consistent with prior work. We found that the vast majority of events showed a clear dynamic component in which modules activated sequentially across the field of view, but only a minority of events were well-fit with a linear traveling wave. We found that spatiotemporal events occur in repeated and stereotyped motifs, reoccurring across hours of imaging. Finally, we found that the most frequently occurring single-frame spatial activity patterns were predictive of future activity patterns over hundreds of milliseconds. Together, our results demonstrate that spontaneous activity in the early developing cortex exhibits a rich spatiotemporal structure, suggesting a potential role in the maturation and refinement of future functional representations.

Significance statement

Understanding the temporal dynamics underlying the network structure in early development is critical for understanding network function and plasticity. By imaging hours of spontaneous cortical activity, we show strong evidence that the vast majority of spontaneous neural activity is dynamic with repeated and complex spatiotemporal patterns with stereotyped structure across hours. This suggests the potential for Hebbian learning in the development and refinement of functional visual representations. We also find that frequently occurring spatial activity patterns are predictive of subsequent activity for up to one second, which may indicate attractor dynamics in spontaneous activity. Our findings characterize key features of the temporal structure of spontaneous activity in visual cortex early in development and deepen our understanding of developing neural networks.
ClOneHORT: Approaches for Improved Fidelity in Generative Models of Synthetic Genomes
Authors: Laboulaye Roland , Borda Victor , Chen Shuo , North Kari E. , Kaplan Robert , O’Connor Timothy D.
Published: June 2024

Motivation

Deep generative models have the potential to overcome difficulties in sharing individual-level genomic data by producing synthetic genomes that preserve the genomic associations specific to a cohort while not violating the privacy of any individual cohort member. However, there is significant room for improvement in the fidelity and usability of existing synthetic genome approaches.

Results

We demonstrate that when combined with plentiful data and with population-specific selection criteria, deep generative models can produce synthetic genomes and cohorts that closely model the original populations. Our methods improve fidelity in the site-frequency spectra and linkage disequilibrium decay and yield synthetic genomes that can be substituted in downstream local ancestry inference analysis, recreating results with .91 to .94 accuracy.

Availability

The model described in this paper is freely available atgithub.com/rlaboulaye/clonehort.
Advancing coral micropropagation for coral restoration and reef engineering
Authors: Walton Emily , Badder Lindsey , Galindo-Martínez Claudia Tatiana , Berry David B. , Tresguerres Martin , Wangpraseurt Daniel
Published: June 2024

In the face of escalating threats posed by human-induced climate change, urgent attention to coral reef restoration is imperative due to ongoing reef degradation. Here, we explored the potential of generating coral micropropagates as a tool to rapidly generate coral tissue for reef restoration and reef engineering. We developed a hypersalinity-induced polyp bailout protocol and a simple attachment device to support the growth of micropropagates on commonly used restoration substrates. We found that hypersalinity induction, at a rate of < 1 ppt hr-1, produced healthy micropropagates of the coralStylophora pistillata. The highest attachment success (∼74%) was achieved in CaCO3substrate devices, which outperformed PVC (∼5%) and Portland cement (∼48%). Settled micropropagates displayed rapid growth rates on both CaCO3(0.037 mm2/day ± 0.002 SE) and PVC (0.057 mm2/day ± 0.008 SE) substrates, while Portland cement induced tissue degradation. Our study provides a detailed methodology for reliably generating, attaching, and growing coral micropropagates and underscores the potential of polyp bailout as a viable technique supporting coral restoration and reef engineering efforts.
Mapping the spectrotemporal regions influencing perception of French stop consonants in noise
Authors: Carranante Géraldine , Cany Charlotte , Farri Pouria , Giavazzi Maria , Varnet Léo
Published: June 2024

Understanding how speech sounds are decoded into linguistic units has been a central research challenge over the last century. This study follows a reverse-correlation approach to reveal the acoustic cues listeners use to categorize French stop consonants in noise. Compared to previous methods, this approach ensures an unprecedented level of detail with only minimal theoretical assumptions. Thirty-two participants performed a speech-in-noise discrimination task based on natural /aCa/ utterances, with C = /b/, /d/, /g/, /p/, /t/, or /k/. The trial-by-trial analysis of their confusions enabled us to map the spectrotemporal information they relied on for their decisions. In place-of-articulation contrasts, the results confirmed the critical role of formant consonant-vowel transitions, used by all participants, and, to a lesser extent, vowel-consonant transitions and high-frequency release bursts. Similarly, for voicing contrasts, we validated the prominent role of the voicing bar cue, with some participants also using formant transitions and burst cues. This approach revealed that most listeners use a combination of several cues for each task, with significant variability within the participant group. These insights shed new light on decades-old debates regarding the relative importance of cues for phoneme perception and suggest that research on acoustic cues should not overlook individual variability in speech perception.
Gestational CBD shapes insular cortex in adulthood
Authors: Iezzi Daniela , Cáceres-Rodríguez Alba , Silva Jessica Pereira , Chavis Pascale , Manzoni Olivier J.
Published: June 2024

Many expectant mothers use CBD to alleviate symptoms like nausea, insomnia, anxiety, and pain, despite limited research on its long-term effects. However, CBD passes through the placenta, affecting fetal development and impacting offspring behavior. We investigated how prenatal CBD exposure affects the insular cortex (IC), a brain region involved in emotional processing and linked to psychiatric disorders. The IC is divided into two territories: the anterior IC (aIC), processing socioemotional signals, and the posterior IC (pIC), specializing in interoception and pain perception. Pyramidal neurons in the aIC and pIC exhibit sex-specific electrophysiological properties, including variations in excitability and the excitatory/inhibitory balance. We investigated IC’s cellular properties and synaptic strength in the offspring of both sexes from mice exposed to low-dose CBD during gestation (E5-E18; 3mg/kg, s.c.). Prenatal CBD exposure induced sex-specific and territory-specific changes in the active and passive membrane properties, as well as intrinsic excitability and the excitatory/inhibitory balance, in the IC of adult offspring. The data indicate that in-utero CBD exposure disrupts IC neuronal development, leading to a loss of functional distinction between IC territories. These findings may have significant implications for understanding the effects of CBD on emotional behaviors in offspring.
SLC7A5 is required for citrulline-dependent growth in arginine limited conditions
Authors: Dunlap Kyle N. , Bender Austin , Bowles Alexis , Bott Alex J. , Rutter Jared , Ducker Gregory S.
Published: June 2024

Tumor cells must optimize metabolite acquisition between synthesis and uptake from their surroundings. The tumor microenvironment is characterized by hypoxia, lactate accumulation, and depletion of many circulating metabolites, including amino acids such as arginine. We performed a metabolism-focused functional screen using CRISPR/Cas9 in a melanoma cell line to identify pathways and factors that enable tumor growth in an arginine-depleted environment. Our screen identified the SLC-family transporter SLC7A5 as required for growth, and we hypothesized that this protein functions as a high-affinity citrulline transporter. Citrulline, an essential precursor to arginine synthesis, is present in human serum at 40 μM and supports localized arginine synthesis across diverse tissues. Using isotopic tracing experiments, we show that citrulline uptake and metabolism are dependent upon expression of this transporter. Pharmacological inhibition of SLC7A5 blocks growth in low arginine conditions across a diverse group of cancer cell lines. Loss of SLC7A5 reduces tumor growth and citrulline import in a mouse tumor model. Overall, we identify a conditionally essential role for SLC7A5 in arginine metabolism as a mediator of citrulline uptake, and we propose that SLC7A5-targeting therapeutic strategies in cancer may be especially effective in the context of arginine limitation.

Key Points

SLC7A5 is required for proliferation in arginine-free conditions when citrulline is present.

SLC7A5 loss impairs arginine metabolism.

Citrulline import is uniquely dependent on SLC7A5.

Small molecule inhibitors of SLC7A5 can be paired with senolytic drugs to drive apoptosis.

SLC7A5knockout decreases citrulline import in a xenograft model.
Cell type-specific regulation by different cytokinetic pathways in the early embryo
Authors: Connors Caroline Q. , Martin Sophia L. , Dumont Julien , Shirasu-Hiza Mimi , Canman Julie C.
Published: June 2024

Cytokinesis, the physical division of one cell into two, is typically assumed to use the same molecular process across animal cells. However, regulation of cell division can vary significantly among different cell types, even within the same multicellular organism. Using six fast-acting temperature-sensitive (ts) cytokinesis-defective mutants, we found that each had unique cell type-specific profiles in the earlyC. elegansembryo. Certain cell types were more sensitive than others to actomyosin and spindle signaling disruptions, disrupting two members of the same complex could result in different phenotypes, and protection against actomyosin inhibition did not always protect against spindle signaling inhibition.
Crispant analysis in zebrafish as a tool for rapid functional screening of disease-causing genes for bone fragility
Authors: Debaenst Sophie , Jarayseh Tamara , de Saffel Hanna , Bek Jan Willem , Boone Matthieu , Josipovic Ivan , Kibleur Pierre , Kwon Ronald Young , Coucke Paul J. , Willaert Andy
Published: June 2024

Heritable Fragile Bone Disorders (FBDs) encompass a spectrum of conditions, from widespread multifactorial to rare monogenic diseases, all characterized by an elevated risk of fractures. The process of validating causative genes and elucidating their pathogenic mechanisms remains a daunting and resource-intensive task. In this study, we evaluated the feasibility of a semi-high throughput zebrafish screening platform for rapid validation andin vivofunctional testing and validation of candidate disease-causing genes for a wide range of heritable FBDs. Six genes associated with severe recessive forms of Osteogenesis Imperfecta (OI) and four genes associated with bone mineral density (BMD), a key osteoporosis indicator, identified through genome-wide association studies (GWAS) were selected. The crispant screening approach, based on CRISPR/Cas9 technology, was used to phenotype directly in F0 mosaic founder zebrafish. Next-Generation Sequencing (NGS) analysis revealed a mean indel efficiency of 88% across ten different crispants, indicating a high proportion of knock-out alleles and thus resembling stable knock-out models. We applied multiple techniques to evaluate skeletal characteristics at 7, 14 and 90 days post-fertilization (dpf), including microscopy for osteoblast reporter visualization and mineralization by Alizarin Red S staining, and microCT for quantitative skeletal analysis. While larval crispants exhibited variable differences in osteoblast-positive and mineralized surface areas, adult-stage crispants displayed more pronounced and consistent skeletal phenotypes. Notably, all crispants developed malformed neural and haemal arches, with a majority presenting vertebral fractures and fusions, and some showing significant alterations in vertebral bone volume and density. In addition,aldh7a1andmbtps2crispants experienced increased mortality due to severe skeletal deformities. RT-qPCR analysis of osteoblast differentiation and bone formation markers at larval stages indicated differential expression of osteogenic markersbglapandcol1a1ain a substantial portion of the crispants, hinting at their utility as biomarkers for FBD crispant screening. In summary, our findings demonstrate that crispant screening in zebrafish offers a viable and efficient strategy for the functional assessment of FBD genes. We advocate for a novel comprehensive approach that integrates various techniques and evaluates distinct skeletal and molecular profiles across different developmental and adult stages. This methodology has the potential to provide new insights into the role of these genes in skeletal biology.
Integrative Transcriptomics Reveals Layer 1 Astrocytes Altered in Schizophrenia
Authors: Leon Julio , Yoshinaga Satoshi , Hino Mizuki , Nagaoka Atsuko , Ando Yoshinari , Moody Jonathan , Kojima Miki , Kitazawa Ayako , Hayashi Kanehiro , Nakajima Kazunori , Condello Carlo , Carninci Piero , Kunii Yasuto , Hon Chung Chau , Shin Jay W. , Kubo Ken-ichiro
Published: June 2024

Schizophrenia is one of the most prevalent psychiatric disorders with unclear pathophysiology despite a century-long history of intense research. Schizophrenia affects multiple networks across different brain regions. The anterior cingulate cortex (ACC) is the region that connects the limbic system to cognitive areas such as the prefrontal cortex and represents a pivotal region for the etiology of schizophrenia; however, the molecular pathology, considering its cellular and anatomical complexity, is not well understood. Here, we performed an integrative analysis of spatial and single-nucleus transcriptomics of the postmortem ACC of people with schizophrenia, together with a thorough histological analysis. The data revealed major transcriptomics signatures altered in schizophrenia, pointing at the dysregulation of glial cells, primarily in astrocytes. We further discovered a decrease in the cellular density and abundance of processes of interlaminar astrocytes, a subpopulation of astrocytes specific to primates that localize in the layer 1 and influence the superficial cortical microenvironment across layer 1 and layers 2/3 of the cortex. Our study suggests that aberrant changes in interlaminar astrocytes could explain the cell-to-cell circuit alterations found in schizophrenia and represent novel therapeutic targets to ameliorate schizophrenia-associated dysfunction.
Confinement, jamming, and adhesion in cancer cells dissociating from a collectively invading strand
Authors: Wang Wei , Law Robert A. , Perez Ipiña Emiliano , Konstantopoulos Konstantinos , Camley Brian A.
Published: June 2024

When cells in a primary tumor work together to invade into nearby tissue, this can lead to cell dissociations—cancer cells breaking off from the invading front—leading to metastasis. What controls the dissociation of cells, and whether they break off singly or in small groups? Can this be determined by cell-cell adhesion or chemotactic cues given to cells? We develop a physical model for this question, based on experiments that mimic aspects of cancer cell invasion using microfluidic devices with microchannels of different widths. Experimentally, most dissociation events (“ruptures”) involve single cells breaking off, but we observe some ruptures of large groups (∼20 cells) in wider channels. The rupture probability is nearly independent of channel width. We recapitulate the experimental results with a phase field cell motility model by introducing three different cell states (follower, guided, and high-motility metabolically active leader cells) based on their spatial position. These leader cells may explain why single-cell rupture is the universal most probable outcome. Our simulation results show that cell-channel adhesion is necessary for cells in narrow channels to invade, and strong cell-cell adhesion leads to fewer but larger ruptures. Chemotaxis also influences the rupture behavior: Strong chemotaxis strength leads to larger and faster ruptures. Finally, we study the relationship between biological jamming transitions and cell dissociations. Our results suggest unjamming is necessary but not sufficient to create ruptures.