bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep Prediction of Human Essential Genes using Weighted Protein-Protein Interaction Networks
Authors: Mehrpou Soroush , Mansoori Eghbal G.
Published: October 2024

Essential proteins are group of proteins that are indispensable to survival and development of cells. Prediction and analysis of essential genes/proteins are crucial for uncovering the mechanisms of cells. Using bioinformatics and high-throughput technologies, forecasting essential genes/proteins by protein–protein interaction (PPI) networks have become more efficient than traditional approaches which use expensive and time-consuming experimental methods. Previous studies have found that the essentiality of genes closely relates to their properties in PPI network. In this work, we propose a supervised deep model for predicting human essential genes using neighboring details of genes/proteins in the PPI network. Our approach implements a weight-biased random walk on PPI network to get the node network context. Then, some different measures are used to get some feature vectors for each node (gene/protein) that preserve the network structure as well as the gene’s properties in the PPI network. These feature vectors are then fed to a Relational AutoEncoder to embed the genes’ features into latent space. At last, these embedded features are put into a trained classifier to predict the human essential genes. The prediction results on two human PPI networks show that our model achieves better performance than those that only refer to genes’ centrality properties in the network.
A multi-omics and cell type-specific characterization of the ventral striatum in human cocaine use disorder
Authors: Zillich Eric , Artioli Annasara , Rossetti Andrea C. , Avetyan Diana , Belschner Hanna , Frank Josef , Stein Frank , Schwarz Jennifer J. , Mechawar Naguib , Turecki Gustavo , Nöthen Markus M. , Hansson Anita C. , Witt Christian C. , Rietschel Marcella , Koch Philipp , Spanagel Rainer , Zillich Lea , Witt Stephanie H.
Published: October 2024

Epigenome, transcriptome, and proteome analyses of postmortem brains have revealed initial molecular insights into cocaine use disorder (CUD). However, the inter-relationship between these –omics and the contribution of individual cell types remain largely unknown. We present an in-depth analysis of molecular changes in the ventral striatum in CUD at multi-omics and single-cell resolution. Integrative multi-omics analyses of microRNA-seq, RNA-seq, and proteomics datasets in 41 individuals and single-nuclei RNA-seq in a subset of 16 individuals revealed conserved deregulation of metabolic pathways, oxidative phosphorylation, and glutamatergic signaling. Cell type-specific analyses identified inverse metabolic pathway deregulation patterns in glial and neuronal cells, notably in astrocytes and medium spiny neurons (MSNs). Characterizing astrocyte-neuron crosstalk revealed altered glutamatergic and cell adhesion signaling in CUD. By applying a comprehensive multi-omics analytical framework, our study provides novel insights into CUD-associated molecular changes in the ventral striatum, suggesting astrocytes, MSNs, and their crosstalk as particularly perturbed in CUD.
Scalable enumeration and sampling of minimal metabolic pathways for organisms and communities
Authors: Øyås Ove , Theorell Axel , Stelling Jörg
Published: October 2024

Many interactions in microbial consortia or tissues of multicellular organisms rely on networks of metabolite exchanges. To predict community function and composition beyond statistical correlations, one can use genome-scale metabolic models. However, comprehensive model analysis via metabolic pathways is a major challenge because pathway counts grow combinatorially with model size. Here, we define minimal pathways that yield compact representations of metabolic network capabilities. They generalize existing pathway concepts by allowing inhomogeneous constraints and targeted analysis of subnetworks, and we show how to enumerate and sample them efficiently via iterative minimization and pathway graphs. This enables applications such as assessing quantitative gene essentiality in the central metabolism ofEscherichia coli, predicting metabolite exchanges associated with homeostasis and health in a host-microbe model of the human gut, and designing butyrate-producing microbial communities. Minimal pathways enable scalable analysis of metabolic subnetworks such as metabolite exchanges in uni- and multicellular systems.
Hand Position Fields of Neurons in the Premotor Cortex of Macaques during Natural Reaching
Authors: Cao Sheng-Hao , Han Xin-Yong , Zhao Zhi-Ping , Gu Jian-Wen , Jiang Tian-Zi , Yu Shan
Published: October 2024

Planning and execution for goal-directed movements requires the integration of the current position of body or body parts with various kinematic parameters of the movement itself. In the hippocampus, the field-based representation of spatial information plays an essential role in this process during navigation. However, if a similar, field-based encoding framework is also utilized by the motor areas during hand reaching remains unclear. In this study, we investigated the hand position tuning in the dorsal premotor cortex (PMd) neurons (n= 601) when four monkeys performing a naturalistic reach-and-grasp task. We show that 132/601 (22%) of PMd neurons increased their firing rates when the monkey’s hand occupied specific positions in the space, forming the “position fields” in their spatial firing maps that can be well described by 2D Gaussian functions/kernels. We further analyzed how the field-tuning of hand position is co-represented with other task-related parameters including the hand moving direction, speed, and reward location in the same population of PMd neurons, revealing a mixed-selective framework also similar to that discovered in the hippocampus. These position-tuned cells demonstrated high efficiency in encoding hand position, with ~10% of overall recorded neurons contributing >80% of accuracy in decoding instantaneous hand moving trajectories. These results suggest that a field-based encoding framework of position may be a common component to representing spatial information and integrating it with kinematic parameters for guiding goal-directed movements of the body or body parts.
Deep generative networks reveal the tuning of neurons in IT and predict their influence on visual perception
Authors: Papale Paolo , De Luca Daniela , Roelfsema Pieter R.
Published: October 2024

Finding the tuning of visual neurons has kept neuroscientists busy for decades. One approach to this problem has been to test specific hypotheses on the relevance of a visual property (e.g. orientation or color), build a set of “artificial” stimuli that vary along that property and then record neural responses to those stimuli. Here, we present a complementary, data-driven method to retrieve the tuning properties of visual neurons. Exploiting deep generative networks and electrophysiology in monkeys, we first used a method to reconstruct any stimulus from its evoked neuronal activity in the inferotemporal cortex (IT). Then, by arbitrarily perturbing the response of individual cortical sites in the model, we generated naturalistic and interpretable sequences of images that strongly influence neural activity of that site. This method enables the discovery of previously unknown tuning properties of high-level visual neurons that are easily interpretable, which we tested with carefully controlled stimuli. When we knew which images drove the neurons, we activated the cells with electrical microstimulation and observed a predicable shift of the monkey perception in the direction of the preferred image. By allowing the brain to tell us what it cares about, we are no longer limited by our experimental imagination.
Medieval genomes from eastern Iberia illuminate the role of Morisco mass deportations in dismantling a long-standing genetic bridge with North Africa
Authors: Oteo-García Gonzalo , Silva Marina , Foody M. George B. , Yau Bobby , Fichera Alessandro , Alapont Llorenç , Justeau Pierre , Rodrigues Simão , Monteiro Rita , Gandini Francesca , Rovira Marisa , Ribera i Lacomba Albert , Beneyto Josep Pascual , Mattiangeli Valeria , Bradley Daniel G. , Edwards Ceiridwen J. , Pala Maria , Richards Martin B.
Published: October 2024

Background

The Islamic influence on the Iberian Peninsula left an enduring legacy culturally and linguistically, however the demographic impact is less well understood. This study aims to explore the dynamics of gene flow and population structure in eastern Iberia from the early to late Medieval period through ancient DNA.

Results

Our comprehensive genomic analysis uncovered gene flow from various Mediterranean regions into Iberia before the Islamic period, supporting a pre-existing pan-Mediterranean homogenization phenomenon during the Roman Empire. North African ancestry is present but sporadic in late antiquity genomes but becomes consolidated during the Islamic period. We uncovered one of the earliest dated Islamic burials in Spain, which showed high levels of inbreeding. For the first time we also prove the persistence of North African ancestry in a Christian cemetery until the 17th century, in addition to evidence of slave traffick from the Maghreb.

Conclusions

This study reveals the complex interaction between political events and cultural shifts that influenced the population of eastern Iberia. It highlights the existence of a slave trade and underscores the lasting impact of historical events, such as the Expulsion of the Moriscos in 1609 CE, on the region’s genetic and cultural landscape through mass population displacement and replacement.
A Graph Neural Network Approach to Investigate Brain Critical States Over Neurodevelopment
Authors: Cabral-Carvalho Rodrigo M. , Pinaya Walter H. L. , Sato João R.
Published: October 2024

Recent studies show that functional resting-state dynamics may be modelled by lattice models near criticality, such as the 2D Ising model. The Ising temperature, which is the control parameter dictating the phase transitions of the model, can provide insight into the large-scale dynamics and is being used to better understand different brain states and neurodevelopment. This period is categorized by intricated changes in the microcircuits to consolidate networks. These changes influence the macroscopic brain dynamics and also its functional relations, which can be observed in functional Magnetic Resonance Imaging (fMRI). Therefore, this work investigates neurodevelopment through a novel method to estimate the Ising temperature of the brain from fMRI data using functional connectivity and Graph Neural Networks (GNNs) trained on Ising model networks. The main finding indicates a statistically significant negative correlation between age and temperature for typically developing children (𝑟 =− 0. 48, 𝑝 < 0. 0001)and also children with Attention deficit/hyperactivity disorder (ADHD) (𝑟 =− 0. 49, 𝑝 < 0. 0001). This study suggests that the brain gets distant from criticality as age increases, leading to a more ordered state.

Author Summary

In this study, we employed Graph Neural Networks to investigate functional connectivity patterns of resting-state fMRI data using the 2D Ising model as a theoretical framework to access critical dynamics. Our key finding is the significant decrease in Ising temperature with age in both typically developing children and those with ADHD, indicating a developmental transition from a high-entropy, disordered state to a more ordered, decreasing the availability of dynamical states that the system can occupy and transit in different conditions. Moreover, this decrease in temperature is crucial as it implies that the brain is moving away from criticality, leading the system to a more sub-critical regime. The correlation coefficients across the groups showed no significant differences, indicating the same developmental trajectory.
Genomic prediction in insects: a case study on wing morphology traits in the jewel waspNasonia vitripennis
Authors: Xia Shuwen , Kiss Gabriella Bukovinszkine , Megens Hendrik-Jan , Groenen Martien A.M. , Zwaan Bas J. , Bijma Piter , Pannebakker Bart A.
Published: October 2024

Background

Biological control is a sustainable strategy to combat agricultural pests. Yet, due to legislation, importing non-native biocontrol agents is increasingly restricted. Thus, selective breeding of biocontrol traits of native species is suggested to enhance performance of existing biocontrol agents. Genomic prediction is a new alternative to exploit genetic variation for improving biocontrol efficacy. This study aims to establish proof-of-principle for genomic prediction in insect biocontrol agents, using wing morphology traits in the parasitoidNasonia vitripennisWalker (Pteromalidae) as a model.

Methods

We performed genomic prediction using a Genomic Best Linear Unbiased Prediction (GBLUP) model, using a total of 1,230 individuals with 8,639 SNPs generated by genotyping-by-sequencing (GBS). We used individuals from two generations from the outbred HVRx population, 717 individuals from generation G169 and 513 from generation G172. To assess genomic prediction accuracy, we used across- generation validation: forward validation for G172 from G169, backward in time validation for G169 from G172, and also 5-fold cross-validation, randomly using one fifth of the population as validiation and the others as training groups.

Results

For size-related traits, including tibia length, wing length, width, and second moment wing area, the accuracy of genomic prediction was close to zero in both across-generation validations, but much higher in 5-fold cross-validation (ranging 0.54-0.68). For the shape-related trait wing aspect ratio, a high accuracy was found for all three validation strategies, with 0.47 for across-generation forward validation, 0.65 for across-generation backward validation, and 0.54 for 5-fold cross-validation.

Conclusion

Promising accuracies were observed for all traits in 5-fold cross-validation, but not in the across-generation validations. Overall, applying genomic selection in insect biocontrol agents with a relative small effective population size seems promising. However, factors such as the biology of insects, the techniques of phenotyping, and costs of large-scale genotyping still challenge the application of genomic selection to biocontrol agents.
Proximity to Visual Stimuli Reduces Post-Saccadic Alpha Lateralisation
Authors: Turner Christopher , Vuckovic Aleksandra , Learmonth Gemma , Fracasso Alessio
Published: October 2024

Posterior alpha lateralisation is a well-established marker of visual spatial attention, with growing evidence suggesting that it may also be linked to oculomotor planning and execution. However, saccades also result in a change in visual input to the fovea, which could be linked to lateralised posterior alpha. In this study, we investigate the interplay between saccade-induced foveal input changes and lateralised posterior alpha by analysing saccades from the cue period of a Posner task and the active feedback period of a neurofeedback task, where visual stimuli were present on screen. Specifically, we examine the impact of saccade landing proximity to visual stimuli and saccade amplitude on post-saccade alpha lateralisation. Consistent with previous research, we observe a general post-saccade alpha lateralisation across both tasks. Importantly, we find that alpha lateralisation is reduced in the neurofeedback task when saccades land close to visual stimuli compared to those landing further away, while saccade amplitude has no significant effect. This investigation highlights the importance of controlling for both eye movements and visual stimuli when investigating alpha lateralisation in fixational tasks. Moreover, it shows how both oculomotor and afferent processing mechanisms affect posterior alpha lateralisation.
Thalamo-frontal connectivity patterns in Tourette Syndrome: Insights from combined intracranial DBS and EEG recordings
Authors: Wehmeyer Laura , Baldermann Juan C. , Pogosyan Alek , Plazas Fernando Rodriguez , Loehrer Philipp Alexander , Bonetti Leonardo , Yassine Sahar , Mühlen Katharina Zur , Schüller Thomas , Kuhn Jens , Visser-Vandewalle Veerle , Tan Huiling , Andrade Pablo
Published: October 2024

Thalamic deep brain stimulation (DBS) has shown clinical improvement for patients with treatment-refractory Tourette Syndrome (TS). Advancing DBS for TS requires identifying reliable electrophysiological markers. Recognising TS as a network disorder, we investigated thalamo-cortical oscillatory connectivity by combining local field potential (LFP) recordings from the DBS thalamic target region using the PerceptTMPC neurostimulator with high-density EEG in eight male TS patients (aged 27 to 38) while stimulation was off. We identified a spatially and spectrally distinct oscillatory network connecting the medial thalamus and frontal regions in the alpha band (8–12 Hz), with connectivity strength negatively correlated with TS symptom severity. Moreover, reduced thalamo-frontal alpha connectivity before tic onset, localised in sensorimotor regions and the inferior parietal cortex, suggests its direct role in tic generation. Importantly, associations with symptoms and pre-tic dynamics were specific to connectivity patterns and not evident in the pure power spectra. These findings underscore the importance of investigating electrophysiological oscillatory connectivity to characterise pathological network connections in TS, potentially guiding stimulation-based interventions and future research on closed-loop DBS for TS.
RIPK2 is crucial for the microglial inflammatory response to bacterial muramyl dipeptide but not to lipopolysaccharide
Authors: Yang Changjun , Machado da Silva Maria Carolina , Howell John A. , Larochelle Jonathan , Liu Lei , Gunraj Rachel E. , Pinheiro de Oliveira Antônio Carlos , Candelario-Jalil Eduardo
Published: October 2024

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is a kinase that plays an essential role in the modulation of innate and adaptive immune responses. As a downstream signaling molecule for nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs), it is implicated in the signaling triggered by recognition of microbe-associated molecular patterns by NOD1/2 and TLRs. Upon activation of these innate immune receptors, RIPK2 mediates the release of pro-inflammatory factors by activating mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB). However, whether RIPK2 is essential for downstream inflammatory signaling following the activation of NOD1/2, TLRs, or both remains controversial. In this study, we examined the role of RIPK2 in NOD2- and TLR4-dependent signaling cascades following stimulation of microglial cells with bacterial muramyl dipeptide (MDP), a NOD2 agonist, or lipopolysaccharide (LPS), a TLR4 agonist. We utilized a highly specific proteolysis targeting chimera (PROTAC) molecule, GSK3728857A, and found dramatic degradation of RIPK2 in a concentration- and time-dependent manner. Importantly, the PROTAC completely abolished MDP-induced increases in iNOS and COX-2 protein levels and pro-inflammatory gene transcription ofNos2,Ptgs2,Il-1β,Tnfα,Il6,Ccl2, andMmp9. However, increases in iNOS and COX-2 proteins and pro-inflammatory gene transcription induced by the TLR4 agonist, LPS, were only slightly attenuated with the GSK3728857A pretreatment. Further findings revealed that the RIPK2 PROTAC completely blocked the phosphorylation and activation of p65 NF-κB and p38 MAPK induced by MDP, but it had no effects on the phosphorylation of these two mediators triggered by LPS. Collectively, our findings strongly suggest that RIPK2 plays an essential role in the inflammatory responses of microglia to bacterial MDP but not to LPS.
A brassinosteroid receptor kinase is required for sex determination in the homosporous fernCeratopteris richardii
Authors: Burow Katelin M. , Yang Xi , Zhou Yun , Dilkes Brian P. , Wisecaver Jennifer H.
Published: October 2024

Most ferns, unlike all seed plants, are homosporous and produce sexually undifferentiated spores. Sex in many homosporous ferns is environmentally regulated by the biosynthesis of antheridiogens. Secreted antheridiogen from female or hermaphrodite gametophytes is perceived by undetermined gametophytes which respond by developing as male. In the fernCeratopteris richardii(Ceratopteris), severalhermaphroditic(her) mutants develop as hermaphrodites even in the presence of antheridiogen. A set of five mutant alleles are tightly linked toher7, a locus of unknown molecular identity. The immense size of the Ceratopteris genome has made efficient identification of the underlying genes a challenge. Here, we used bulked segregant RNA-seq (BSR-Seq) to map twohermutants (her7-14andher7-19) to a 16 Mbp interval on chromosome 29 of the Ceratopteris genome. A brassinosteroid receptor-like kinase (BRL) within this interval encoded a deletion mutation inher7-14and a missense mutation inher7-19. Three other linkedhermutants (her7-1,her7-11, andher7-15) encoded missense mutations in the same gene, which we name HER7, providing strong support for HER7 being required for antheridiogen-mediated sex determination in Ceratopteris. HER7-GFP fusion protein is localized in the plasma membrane and cytoplasm, consistent with its predicted function as a brassinosteroid receptor kinase. RNA-seq analysis of gene expression shows that numerous transcripts encoding enzymes, including those for brassinosteroid biosynthesis, accumulate in hermaphrodites compared to male gametophytes. The antheridiogen of Ceratopteris is currently unknown and our finding that a BRL mutant is insensitive to antheridiogen suggests that antheridiogen in Ceratopteris may be a brassinosteroid. Additional work is required to fully resolve the sex determination pathway and determine the chemical composition of antheridiogen in this species. Our work demonstrates we can identify the molecular basis of mutants in large genomes, such as those in homosporous ferns, which can be further applied to the extensive remaining collection of mutants in Ceratopteris.
Structure-Function Relationship of the Ryanodine Receptor Cluster Network in Sinoatrial Node Cells
Authors: Maltsev Alexander V , Subirachs Valeria Ventura , Monfredi Oliver , Juhaszova Magdalena , Warrier Pooja Ajay , Rakshit Shardul , Tagirova Syevda , Maltsev Anna V , Stern Michael D , Lakatta Edward G , Maltsev Victor A
Published: October 2024

The rate of spontaneous action potentials (APs) generated by sinoatrial node cells (SANC) is regulated by local Ca2+release (LCR) from the sarcoplasmic reticulum via Ca2+release channels (ryanodine receptors, RyRs). LCR events propagate and self-organize within the network of RyR clusters (Ca release units, CRUs) via Ca-induced-Ca-release (CICR) that depends on CRU sizes and locations: while larger CRUs generate stronger release signals, the network’s topology governs signal diffusion and propagation. This study used super-resolution structured illumination microscopy to image the 3D network of CRUs in rabbit SANC. The peripheral CRUs formed a spatial mesh, reflecting the cell surface geometry. Two distinct subpopulations of CRUs were identified within each cell, with size distributions conforming to a two component Gamma mixture model. Furthermore, neighboring CRUs exhibited repulsive behavior. Functional properties of the CRU network were further examined in a novel numerical SANC model developed using our experimental data. Model simulations revealed that heterogeneities in both CRU sizes and locationsfacilitateCICR and increase AP firing rate in a cooperative manner. However, these heterogeneities reduce the effect of β-adrenergic stimulation in terms of itsrelative changein AP firing rate. The presence of heterogeneities in both sizes and locations allows SANC to reach higherabsolute AP firing ratesduring β-adrenergic stimulation. Thus, the CICR facilitation by heterogeneities in CRU sizes and locations regulates and optimizes cardiac pacemaker cell operation under various physiological conditions. Dysfunction of this optimization could be a key factor in heart rate reserve decline in aging and disease.
Melanocortin 4 Receptor-Dependent Mechanism of ACTH in Preventing Anxiety-Like Behaviors and Normalizing Astrocyte Proteins After Early Life Seizures
Authors: Khalife Mohamed R. , Villarin Colin , Ruiz Juan Manuel , McClelland Sam A. , Rabbo Khalil Abed , Mahoney J. Matthew , Scott Rod C. , Hernan Amanda E.
Published: October 2024

Epilepsy, affecting millions globally, often leads to significant cognitive and psychiatric comorbidities, particularly in children. Anxiety and depression are particularly prevalent, with roughly a quarter of pediatric epilepsy patients having a comorbid diagnosis. Current treatments inadequately address these issues. Adrenocorticotropic hormone (ACTH), a melanocortin peptide, has shown promise in mitigating cognitive deficits after early life seizures (ELS), potentially through mechanisms beyond its canonical action on melanocortin 2 receptor (MC2R). This study explores the hypothesis that recurrent ELS is associated with long-term anxiety, and that treatment with ACTH can prevent this anxiety through a mechanism that involves melanocortin 4 receptors (MC4R) in the brain. Our findings reveal that ACTH ameliorates anxiety-like behavior associated with ELS, without altering seizure parameters, in wildtype (WT) mice but not in MC4R knockout (KO) mice. Our findings also show that knocking-in MC4R in either neurons or astrocytes was able to rescue the anxiety-like behavior after ACTH treatment. Further, our results show that ACTH normalizes important astrocytic proteins like Glial Fibrillary Acidic Protein (GFAP) and Aquaporin-4 (AQP4) after ELS. This suggests that ACTH’s beneficial effects on anxiety are mediated through MC4R activation in both neuronal and astrocytic populations. This study underscores the therapeutic potential of targeting MC4R in epilepsy treatment, highlighting its role in mitigating cognitive impairments and anxiety-like behaviors associated with ELS.
Reliable reconstruction of cricket song from biophysical models and preserved specimens
Authors: Weiner Ryan , Duke Sarah , Simonelli Gabriella , Bailey Nathan W. , Mhatre Natasha
Published: October 2024

Predicting the function of a biological structure solely from its morphology can be a very powerful tool in several fields of biology, but especially in evolutionary reconstruction. In the field of invertebrate acoustic communication, reconstructing the acoustic properties of sound-producing forewings in crickets has been based on two very divergent methods, finite element modelling (FEM) and vibrometric measurements from preserved specimens. Both methods, however, make strong simplifying assumptions which have not been tested and the reliability of inferences made from either method remains in question. Here we rigorously test and refine both reconstruction methods using the well-knownTeleogryllus oceanicusmodel system and determine the appropriate conditions required to reconstruct the vibroacoustic behaviour of male forewings. We find that when using FEM it is not necessary to assume simplified boundary conditions if the appropriate parameters are found. When using preserved specimens, we find that the sample needs to be rehydrated for reliable reconstruction, however, it may be possible to accomplish rehydrationin silicousing FEM. Our findings provide a refined methodology for the reliable reconstruction of cricket songs, whether from fossils or preserved specimens from museums or field collections.
Intranasal hemagglutinin protein boosters induce robust mucosal immunity and cross-protection against influenza A viral challenge
Authors: Moriyama Miyu , Rodrigues Gisele , Wang Jiping , Hudak Andrew , Dong Huiping , Homer Robert J. , Weissman Drew , Ma Shuangge , Iwasaki Akiko
Published: October 2024

Licensed parenteral influenza vaccines induce systemic antibody responses and alleviate disease severity but do not efficiently prevent viral entry and transmission due to the lack of local mucosal immune responses. Here, we describe intranasal booster strategy with unadjuvanted recombinant hemagglutinin (HA) following initial mRNA-LNP vaccination, Prime and HA. This regimen establishes highly protective HA-specific mucosal immune memory responses in the respiratory tract. Intranasal HA boosters provided significantly reduced viral replication compared to parenteral mRNA-LNP boosters in both young and old mice. Correlation analysis revealed that slightly increased levels of nasal IgA are significantly associated with a reduced viral burden in the upper respiratory tract. Intranasal boosting with an antigenically distinct H1 HA conferred sterilizing immunity against heterologous H1N1 virus challenge. Additionally, a heterosubtypic intranasal H5 HA booster elicited cross-reactive mucosal humoral responses. Our work illustrates the potential of a nasal HA protein booster as a needle- and adjuvant-free strategy to prevent infection and disease from influenza A viruses.

One Sentence Summary

Adjuvant-free nasal booster induces protective immunity against influenza infection.
Decoding the Unintelligible: Neural Speech Tracking in Low Signal-to-Noise Ratios
Authors: He Xiaomin , Raghavan Vinay S , Mesgarani Nima
Published: October 2024

Understanding speech in noisy environments is challenging for both human listeners and speech technologies, with significant implications for hearing aid design and communication systems. Auditory attention decoding (AAD) aims to decode the attended talker from neural signals to enhance their speech and improve perception. However, whether this decoding remains reliable under severely degraded listening conditions remains unclear. In this study, we investigated selective neural tracking of the attended speaker under adverse listening conditions. Using EEG recordings in a multi-talker speech perception task with varying SNR, participants’ task performance—quantified through a repeated-word detection task—was analyzed as a proxy for perceptual accuracy and attentional focus, while neural responses were used to decode the attended talker. Despite substantial degradation in task performance, we found that neural tracking of attended speech persists, suggesting that the brain retains sufficient information for decoding. These findings demonstrate that even in highly challenging conditions, AAD remains feasible, offering a potential avenue for improving speech perception in brain-informed audio technologies, such as hearing aids, that leverage AAD to enhance listening experiences in real-world noisy environments.
A diffusion model conditioned on compound bioactivity profiles for predicting high-content images
Authors: Cook Steven , Chyba Jason , Gresoro Laura , Quackenbush Doug , Qiu Minhua , Kutchukian Peter , Martin Eric J. , Skewes-Cox Peter , Godinez William J.
Published: October 2024

High-content imaging (HCI) provides a rich snapshot of compound-induced phenotypic outcomes that augment our understanding of compound mechanisms in cellular systems. Generative imaging models for HCI provide a route towards anticipating the phenotypic outcomes of chemical perturbations in silico at unprecedented scale and speed. Here, we developed Profile-Diffusion (pDIFF), a generative method leveraging a latent diffusion model conditioned on in silico bioactivity profiles to predict high-content images displaying the cellular outcomes induced by compound treatment. We trained and evaluated a pDIFF model using high-content images from a Cell Painting assay profiling 3750 molecules with corresponding in silico bioactivity profiles. Using a realistic held-out set, we demonstrate that pDIFF provides improved predictions of phenotypic responses of compounds with low chemical similarity to compounds in the training set compared to generative models trained on chemical fingerprints only. In a virtual hit expansion scenario, pDIFF yielded significantly improved expansion outcomes, thus showcasing the potential of the methodology to speed up and improve the search for novel phenotypically active molecules.
Microscopic deconstruction of cortical circuit stimulation by transcranial ultrasound
Authors: Lemaire Théo , Yuan Yi , Gellman Celia , LeMessurier Amy M. , Haiken Dray Sarah R. , Little Justin P. , Froemke Robert C. , Shoham Shy
Published: October 2024

Transcranial Ultrasound Stimulation (TUS) can noninvasively and reversibly perturb neuronal activity, but the mechanisms by which ultrasound engages brain circuits to induce functional effects remain unclear. To elucidate these interactions, we applied TUS to the cortex of awake mice and concurrently monitored local neural activity at the acoustic focus with two-photon calcium imaging. We show that TUS evokes highly focal responses in three canonical neuronal populations, with cell-type-specific dose dependencies. Through independent parametric variations, we demonstrate that evoked responses collectively scale with the time-average intensity of the stimulus. Finally, using computational unmixing we propose a physiologically realistic cortical circuit model that predicts TUS-evoked responses as a result of both direct effects and local network interactions. Our results provide a first direct evidence of TUS’s focal effects on cortical activity and shed light on the complex circuit mechanisms underlying these effects, paving the way for TUS’s deployment in clinical settings.
mRNA-based influenza vaccine expands breadth of B cell response in humans
Authors: Matz Hanover C. , Yu Tae-Geun , Zhou Julian Q. , Peyton Lowrey , Madsen Anders , Han Fangjie , Schmitz Aaron J. , Horvath Stephen C. , Dixit Kritika , Keplinger Hunter K. , Strnad Benjamin S. , Hoegger Mark J. , Middleton William D. , Klebert Michael K. , Lin Nina H. , Nachbagauer Raffael , Paris Robert , Turner Jackson S. , Presti Rachel M. , Lee Jiwon , Ellebedy Ali H.
Published: October 2024

Summary paragraph

Eliciting broad and durable antibody responses against rapidly evolving pathogens like influenza viruses remains a formidable challenge1,2. The germinal center (GC) reaction enables the immune system to generate broad, high-affinity, and durable antibody responses to vaccination3–5. mRNA-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines induce persistent GC B cell responses in humans6–9. Whether an mRNA-based influenza vaccine could induce a superior GC response in humans compared to the conventional inactivated influenza virus vaccine remains unclear. We assessed B cell responses in peripheral blood and draining lymph nodes in cohorts receiving the inactivated or mRNA-based quadrivalent seasonal influenza vaccine. Participants receiving the mRNA-based vaccine produced more robust plasmablast responses and higher antibody titers to H1N1 and H3N2 influenza A viruses and comparable antibody titers against influenza B virus strains. Importantly, mRNA-based vaccination stimulated robust recall B cell responses characterized by sustained GC reactions that lasted at least 26 weeks post-vaccination in three of six participants analyzed. In addition to promoting the maturation of responding B cell clones, these sustained GC reactions resulted in enhanced engagement of low-frequency pre-existing memory B cells, expanding the landscape of vaccine-elicited B cell clones. This translated to expansion of the serological repertoire and increased breadth of serum antibody responses. These findings reveal an important role for the induction of persistent GC responses to influenza vaccination in humans to broaden the repertoire of vaccine-induced antibodies.
Recent codon preference reversals in theDrosophila melanogasterlineage
Authors: Yamashita Haruka , Matsumoto Tomotaka , Kawashima Kent , Daanaa Hassan Sibroe Abdulla , Yang Ziheng , Akashi Hiroshi
Published: October 2024

Nearly neutral evolutionary dynamics may be prevalent in genome evolution but the functional effects of weakly selected mutations generally lie outside the range of direct measurement. Synonymous codon usage bias is well-suited for population genetic inference; under major codon preference, translationally superior “major” codons confer fitness benefits relative to their less efficiently and/or accurately decoded synonymous counterparts. The fitness benefits of major codons are likely vanishingly small, but common selective forces among genes justify pooling of mutations with predicted fitness effects to confer statistical power to detect footprints of directional forces. In naturally occurring variation fromDrosophila simulans,minor to major codon mutations segregate at higher frequencies within populations than major to minor changes. In contrast, inDrosophila melanogaster, codon family-specific polymorphism patterns reveal a reduced efficacy of natural selection in most synonymous families, but surprisingly, support reversals of favored states in the four codon families encoded by NAY. These codon families show accelerated synonymous fixations in favor of NAT codons deeper in the gene tree, within the ancestralD. melanogasterlineage. Differences for both allele frequencies and fixation rates are greater among X-linked, relative to autosomal, loci. These four lines of evidence are best explained by fitness effect reversals and illustrate how fine-scale sequence pattern analyses can reveal ongoing genome-wide adaptation and motivate experimental investigations of novel function. The correspondence between reversed selection and wobble position queuosine modification in NAY cognate tRNAs is intriguing, but the phenotypic basis of reversals remains unclear.
Effects of SSRIs on the spatial transcriptome of dorsal raphe serotonin neurons
Authors: Henningson Charlotta , Mlost Jakub , Dorocic Iskra Pollak
Published: October 2024

The serotonin system is the main therapeutic target for selective serotonin reuptake inhibitors (SSRIs) in treating depression, yet their mechanism of action remains incompletely understood. To investigate the molecular and transcriptional effects of SSRI administration on serotonin neurons, we performed spatial transcriptomics, a spatially resolved RNA sequencing method in intact brain tissue. Mouse brain sections containing the dorsal raphe nucleus and adjacent midbrain structures were analyzed, revealing six distinct serotonergic subpopulations with unique molecular signatures and spatial distributions. Both acute and chronic fluoxetine treatment induced a large number of changes in gene expression in the dorsal raphe nucleus. Notably, Htr1a expression increased following acute treatment but decreased after chronic administration, aligning with previous findings on serotonin transporter blockade effects on 5HT1a autoreceptors. Gene enrichment and network analysis identified key pathways modulated by SSRI administration, including Ras, MAPK and cAMP signalling pathways as well as pathways involved in axonal guidance. Additionally, we observed treatment-dependent opposing transcriptional changes in neuropeptides, particularly thyrotropin-releasing hormone (Trh) and Prodynorphin (Pdyn), with distinct spatial localization within the dorsal raphe nucleus. Collectively, our transcriptomic and in situ hybridization analyses reveal spatial and cell-type-specific heterogeneity in SSRI action within the dorsal raphe nucleus, providing new insights into the molecular basis of SSRI treatment effects.
Reduction of SynGAP-γ, disrupted splicing ofAgap3, and oligodendrocyte deficits inSrrm2mice, a genetic model of schizophrenia and neurodevelopmental disorder
Authors: Aryal Sameer , Geng Chuhan , Kwon Min Jee , Farsi Zohreh , Goble Nathaniel , Asan Ahmet S. , Brenner Kira , Shepard Nate , Seidel Olivia , Wang Yining , Nicolella Ally , Song Bryan J. , Keshishian Hasmik , Carr Steven A. , Pan Jen Q. , Sheng Morgan
Published: October 2024

Rare loss-of-function (LoF) variants inSRRM2, which encodes the SRRM2 splicing factor, are associated with schizophrenia and a neurodevelopmental disorder. How haploinsufficiency ofSRRM2leads to brain dysfunction is unknown. We find thatSrrm2+/-mice display (i) large-scale changes in gene expression in neuronal and glial cells, affecting synapse-related and other common molecular pathways across multiple brain regions, (ii) reduction of multiple key postsynaptic proteins, including the gamma isoform of SynGAP, itself encoded by a neurodevelopmental disorder risk gene, (iii) abnormal splicing and elevated expression of Agap3, a SynGAP interactor, (iv) reduced numbers of oligodendrocytes accompanied by decreased expression of myelin-related mRNAs and proteins, and (v) behavioral and EEG abnormalities, including reduction in sleep spindles that phenocopy humans with schizophrenia. Our findings provide insights into the molecular and neurobiological mechanisms of and potential therapeutic avenues for schizophrenia and theSRRM2LoF neurodevelopmental disorder.
Submillimeter diffusion MRI using an in-plane segmented 3D multi-slab acquisition and denoiser-regularized reconstruction
Authors: Li Ziyu , Zhu Silei , Miller Karla L. , Wu Wenchuan
Published: October 2024

High-resolution diffusion MRI (dMRI) provides valuable insights into brain microstructure, particularly at submillimeter resolutions, where it enables more precise delineations of curved and crossing white matter pathways. However, achieving high-quality submillimeter dMRI in-vivo poses significant challenges due to the intrinsically low signal-to-noise ratio (SNR), along with the long echo spacing, readout time, and TE required for the large matrix size, leading to significant image distortion, T2* blurring, and T2 signal decay. In this study, we propose a novel acquisition and reconstruction framework to overcome these challenges. Based on numerical simulations, we introduce an in-plane segmented 3D multi-slab acquisition that leverages the optimal SNR efficiency of 3D multi-slab imaging while reducing echo spacing, readout times, and TE using in-plane segmentation. This approach minimizes distortion, improves image sharpness, and enhances SNR. Additionally, we develop a denoiser-regularized reconstruction to suppress noise while maintaining data fidelity, which reconstructs high-SNR images without introducing substantial blurring or bias. Comprehensive in-vivo experiments demonstrate that our method consistently produces high-quality dMRI data at 0.65 mm and 0.53 mm isotropic resolutions on a 3T scanner. The submillimeter dMRI datasets reveal richer microstructural details, reduce gyral bias, and improve U-fiber mapping compared to prospectively acquired 1.22 mm diffusion data. Our method demonstrates robustness at 7T and generates high-SNR 0.61 mm diffusion datasets, showing excellent agreement with previous post-mortem studies at the same scanner. Implemented using the open-source, scanner-agnostic framework Pulseq, our approach may facilitate broader adoption across different scanner platforms to benefit a wider range of applications. These results underscore the potential of our method to advance medical image analysis and neuroscientific research on human brain connectivity.
TENM4 is an essential transduction component for touch and pain
Authors: Khallaf Mohammed A. , Huang Angela Tzu-Lun , Dalmasso Letizia , Chakrabarti Sampurna , Groeneveld Rowena , Sierra Yinth Andrea Bernal , Garcia-Contreras Jonathan Alexis , Schütz Anja , Bégay Valérie , Hedtrich Sarah , Zhong Wei , Popp Oliver , Mertins Philipp , Lewin Gary R.
Published: October 2024

A gentle touch or a painful pinch are relayed to the brain and spinal cord by rapidly conducting myelinated sensory neurons1,2. These sensory neurons possess mechanically activated ion channels like PIEZO2 and ELKIN1 that can be gated by small movements of the substrate3–6. This gating mechanism has been proposed to involve extracellular tether proteins that may transfer force from the matrix to the channel7, the so-called force from tether model8. The molecular nature of such tethers has, however, remained elusive. Here we identify the type II membrane protein Teneurin-4 (TENM4) as an essential component for mechanosensory transduction in the vast majority of cutaneous mechanoreceptors, including fast conducting nociceptors. Sensory neuron specific genetic ablation ofTenm4in mice led to profound touch insensitivity. We devised a strategy to rapidly and reversibly disassemble the TENM4 protein at sensory endings, demonstrating its direct involvement in sensory transduction. TENM4 has been primarily studied in the context of neural development, but here we provide evidence that it transfers force to mechanically activated channels like PIEZO2 and ELKIN1, with which it associates. The identification of TENM4 as an essential component of fast somatic sensation including fast mechanical nociception is a major step towards identifying treatments for sensory disorders including pain.
Filopodia-like Structures are Essential for Steroid Release
Authors: Simon Eleanor , Bonche Raphael , Maarouf Yassine , Nawrot-Esposito Marie-Paule , Romero Nuria Magdalena
Published: October 2024

Steroid hormones, crucial for development and physiology, were traditionally believed to diffuse passively through membranes. However, recent evidence shows insect steroid ecdysone being secreted via regulated exocytosis, but the mechanisms ensuring successful hormone release into circulation remain unclear. Our study identifies specialized membrane protrusions, filopodia-like structures named "hormonemes," in the Drosophila prothoracic gland as essential for steroid vesicle release. Confocal imaging reveals that these actin- and tubulin-rich structures form a membrane-intertwined basal domain critical for secretion. Disrupting filopodia by interfering with BM interactions, perlecan or beta-integrin, or filopodia-specific protein expression, alpha-actinin, significantly reduces ecdysone signaling by impairing its release, despite proper production in the gland. Additionally, filopodia dynamics, such as length and density, align with secretion timing and hormone circulating levels, suggesting their role in synchronizing release with physiological needs. The systematic presence of membrane protrusions in steroid-secreting glands across species prompts a comprehensive re-evaluation of steroid release mechanisms.