bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractMost 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

ABSTRACTThe 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

AbstractEpilepsy, 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

AbstractPredicting 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

AbstractLicensed 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 SummaryAdjuvant-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

AbstractUnderstanding 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

AbstractHigh-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

ABSTRACTTranscranial 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 paragraphEliciting 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

AbstractNearly 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.
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

AbstractRare 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

AbstractHigh-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

AbstractA 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.