bluuebunny/crossref_metadata_2025_split huggingface dataset:
MBL-1/Muscleblind regulates neuronal differentiation and controls the splicing of a terminal selector inCaenorhabditis elegans
Authors: Lee Ho Ming Terence , Lim Hui Yuan , He Haoming , Lau Chun Yin , Zheng Chaogu 
Published: May 2024

AbstractThe muscleblind family of mRNA splicing regulators is conserved across species and regulate the development of muscles and the nervous system. However, how Muscleblind proteins regulate neuronal fate specification and neurite morphogenesis at the single-neuron level is not well understood. In this study, we found that theC. elegansMuscleblind/MBL-1 promotes axonal growth in the touch receptor neurons (TRNs) by regulating microtubule stability and polarity. Transcriptomic analysis identified dozens of MBL-1-controlled splicing events in genes related to neuronal differentiation or microtubule functions. Among the MBL-1 targets, the LIM-domain transcription factormec-3is the terminal selector for the TRN fate and induces the expression of many TRN terminal differentiation genes. MBL-1 promotes the splicing of themec-3long isoform, which are essential for TRN fate specification, and inhibits the short isoforms that have much weaker activities in activating downstream genes. MBL-1 promotesmec-3splicing through three “YGCU(U/G)Y” motifs located downstream of the included exon, which is similar to the mechanisms used by mammalian Muscleblind and suggests a deeply conserved context-dependency of the splicing regulation. Interestingly, the expression ofmbl-1in the TRNs is dependent on themec-3long isoform, indicating a positive feedback loop between the splicing regulator and the terminal selector. Finally, through a forward genetic screen, we found that MBL-1 promotes neurite growth partly by inhibiting the DLK-1/p38 MAPK pathway. In summary, our study provides mechanistic understanding of the role of Muscleblind in regulating cell fate specification and neuronal morphogenesis.
Multimodal analyses of immune cells during bone repair identify macrophages as a therapeutic target in musculoskeletal trauma
Authors: Hachemi Yasmine , Perrin Simon , Ethel Maria , Julien Anais , Vettese Julia , Geisler Blandine , Göritz Christian , Colnot Céline 
Published: May 2024

AbstractMusculoskeletal traumatic injuries (MTI) involve soft tissue lesions adjacent to a bone fracture leading to fibrous nonunion. The impact of MTI on the inflammatory response to fracture and on the immunomodulation of skeletal stem/progenitor cells (SSPCs) remains unknown. Here, we used single cell transcriptomic analyses to describe the immune cell dynamics after bone fracture and identified distinct macrophage subsets with successive pro-inflammatory, pro-repair and anti-inflammatory profiles. Concurrently, SSPCs transition via a pro- and anti-inflammatory fibrogenic phase of differentiation prior to osteochondrogenic differentiation. In a preclinical MTI mouse model, the injury response of immune cells and SSPCs is disrupted leading to a prolonged pro-inflammatory phase and delayed resolution of inflammation. Macrophage depletion improves bone regeneration in MTI demonstrating macrophage involvement in fibrous nonunion. Finally, pharmacological inhibition of macrophages using the CSF1R inhibitor Pexidartinib ameliorates healing. These findings reveal the coordinated immune response of macrophages and skeletal stem/progenitor cells as driver of bone healing and as a primary target for the treatment of trauma-associated fibrosis.SummaryHachemi et al. report the immune cell atlas of bone repair revealing macrophages as pro-fibrotic regulators and a therapeutic target for musculoskeletal regeneration. Genetic depletion or pharmacological inhibition of macrophages improves bone healing in musculoskeletal trauma.
An integrative taxonomy approach reveals Saccharomyces chiloensis sp. nov. as a newly discovered species from Coastal Patagonia
Authors: Peña Tomas A. , Villarreal Pablo , Agier Nicolas , Chiara Matteo De , Barría Tomas , Urbina Kamila , Villarroel Carlos A. , Santos Ana R. O. , Rosa Carlos A. , Nespolo Roberto F. , Liti Gianni , Fischer Gilles , Cubillos Francisco A. 
Published: May 2024

ABSTRACTSpecies delineation in microorganisms is challenging due to the limited markers available for accurate species assignment. Here, we applied an integrative taxonomy approach, combining extensive sampling, whole-genome sequence-based classification, phenotypic profiling, and assessment of interspecific reproductive isolation. Our work reveals the presence of a distinctSaccharomyceslineage inNothofagusforests of coastal Patagonia. This lineage, designatedSaccharomyces chiloensissp. nov., exhibits 7% genetic divergence from its sister speciesS. uvarum, as revealed by whole-genome sequencing and population analyses. The South America-C (SA-C) coastal Patagonia population forms a unique clade closely related to a previously described divergentS. uvarumpopulation from Oceania (AUS, found in Australia and New Zealand). Our species reclassification is supported by a low Ortho Average Nucleotide Identity (OANI) of 93% in SA-C and AUS relative toS. uvarum, which falls below the suggested species delineation threshold of 95%, indicating an independent evolutionary lineage. Hybrid spore viability assessment provided compelling evidence that SA-C and AUS are reproductively isolated fromS. uvarum. In addition, we found unique structural variants betweenS. chiloensissp. nov. lineages, including large-scale chromosomal translocations and inversions, together with a distinct phenotypic profile, emphasizing their intraspecies genetic distinctiveness. We suggest thatS. chiloensissp. nov diverged fromS. uvarumin allopatry due to glaciation, followed by post-glacial dispersal, resulting in distinct lineages on opposite sides of the Pacific Ocean. The discovery ofS. chiloensissp. nov. illustrates the uniqueness of Patagonia’s coastal biodiversity and underscores the importance of adopting an integrative taxonomic approach in species delineation to unveil cryptic microbial species. The holotype ofS. chiloensissp. nov. is CBS 18620T.
Feathers of Grace: The “After You” Gesture in Japanese Tits
Authors: Da Silva Sergio , Matsushita Raul 
Published: May 2024

AbstractA recent study found evidence of symbolic gesture use in Japanese tits (Parus minor). The study reveals how these birds use wing-fluttering movements to transmit an “after you” to their partners, implying a degree of cognitive skill previously thought to be unique to humans and great apes. If confirmed, this research contradicts long-held notions about animal communication by proving that Japanese tits not only participate in intricate vocal communications, which can comprise phrases with specific grammatical rules, but also use body language as a form of engagement. Here, we evaluate this claim by inspecting the data and utilizing bootstrapping to expand the sample size. We find a large variation in how frequently the “after you” gesture is employed in different bootstrap samples, suggesting that while the gesture is a consistent behavior, its frequency can vary significantly. Moreover, the timing of the male’s response to the female’s gesture can fluctuate, though the response itself appears to be a stable phenomenon. Because the frequency of the “after you” gesture varied greatly, especially in light of potential cognitive and other biases influencing the study, this bold claim should be taken with caution.
Bridging Auditory Perception and Natural Language Processing with Semantically informed Deep Neural Networks
Authors: Esposito Michele , Valente Giancarlo , Plasencia-Calaña Yenisel , Dumontier Michel , Giordano Bruno L. , Formisano Elia 
Published: May 2024

AbstractSound recognition is effortless for humans but poses a significant chal-lenge for artificial hearing systems. Deep neural networks (DNNs), especially convolutional neural networks (CNNs), have recently sur-passed traditional machine learning in sound classification. However, current DNNs map sounds to labels using binary categorical variables, neglecting the semantic relations between labels. Cognitive neuroscience research suggests that human listeners exploit such semantic informa-tion besides acoustic cues. Hence, our hypothesis is that incorporating semantic information improves DNN’s sound recognition performance, emulating human behavior. In our approach, sound recognition is framed as a regression problem, with CNNs trained to map spec-trograms to continuous semantic representations from NLP models (Word2Vec, BERT, and CLAP text encoder). Two DNN types were trained: semDNN with continuous embeddings and catDNN with cat-egorical labels, both with a dataset extracted from a collection of 388,211 sounds enriched with semantic descriptions. Evaluations across four external datasets, confirmed the superiority of semantic labeling from semDNN compared to catDNN, preserving higher-level relations. Importantly, an analysis of human similarity ratings for natural sounds, showed that semDNN approximated human listener behavior better than catDNN, other DNNs, and NLP models. Our work contributes to understanding the role of semantics in sound recognition, bridging the gap between artificial systems and human auditory perception.
Induction of Hepatitis B Core Protein Aggregation Targeting an Unconventional Binding Site
Authors: Khayenko Vladimir , Makbul Cihan , Schulte Clemens , Hemmelmann Naomi , Kachler Sonja , Böttcher Bettina , Maric Hans M. 
Published: May 2024

AbstractThe hepatitis B virus (HBV) infection is a major global health problem, with chronic infection leading to liver complications and high death toll. Current treatments, such as nucleos(t)ide analogs and interferon-α, effectively suppress viral replication but rarely cure the infection. To address this, new antivirals targeting different components of the HBV molecular machinery are being developed. Here we investigated the hepatitis B core protein (HBc) that forms the viral capsids and plays a vital role in the HBV life cycle. We explored two distinct binding pockets on the HBV capsid: the central hydrophobic pocket of HBc-dimers and the pocket at the tips of capsid spikes. We synthesized a geranyl dimer that binds to the central pocket with micromolar affinity, and dimeric peptides that bind the spike-tip pocket with sub-micromolar affinity. Cryo-electron microscopy further confirmed the binding of peptide dimers to the capsid spike tips and their capsid-aggregating properties. Finally, we show that the peptide dimers induce HBc aggregation in vitro and in living cells. Our findings highlight two tractable sites within the HBV capsid and provide an alternative strategy to affect HBV capsids.
Molecular basis for plasma membrane recruitment of PI4KA by EFR3
Authors: Suresh Sushant , Shaw Alexandria L , Pemberton Joshua G , Scott Mackenzie K , Harris Noah J , Parson Matthew AH , Jenkins Meredith L , Rohilla Pooja , Alvarez-Prats Alejandro , Balla Tamas , Yip Calvin K , Burke John E 
Published: May 2024

AbstractThe lipid kinase phosphatidylinositol 4 kinase III alpha (PI4KIIIα/PI4KA) is a master regulator of the lipid composition and asymmetry of the plasma membrane. PI4KA exists primarily in a heterotrimeric complex with its regulatory proteins TTC7 and FAM126. Fundamental to PI4KA activity is its targeted recruitment to the plasma membrane by the lipidated proteins EFR3A and EFR3B. Here, we report a cryo-EM structure of the C-terminus of EFR3A bound to the PI4KA-TTC7B-FAM126A complex, with extensive validation using both hydrogen deuterium exchange mass spectrometry (HDX-MS), and mutational analysis. The EFR3A C-terminus undergoes a disorder-order transition upon binding to the PI4KA complex, with an unexpected direct interaction with both TTC7B and FAM126A. Complex disrupting mutations in TTC7B, FAM126A, and EFR3 decrease PI4KA recruitment to the plasma membrane. Multiple post-translational modifications and disease linked mutations map to this site, providing insight into how PI4KA membrane recruitment can be regulated and disrupted in human disease.One sentence summaryThe cryo-EM structure of the C-terminus of EFR3A bound to the PI4KA complex reveals the molecular mechanism underlying PI4KA membrane localisation, and provides novel insight into PI4KA regulation and its involvement in human disease.
Single-cell transcriptomics reveals evolutionary reconfiguration of embryonic cell fate specification in the sea urchinHeliocidaris erythrogramma
Authors: Massri Abdull J. , Berrio Alejandro , Afanassiev Anton , Greenstreet Laura , Pipho Krista , Byrne Maria , Schiebinger Geoffrey , McClay David R. , Wray Gregory A. 
Published: May 2024

AbstractAltered regulatory interactions during development likely underlie a large fraction of phenotypic diversity within and between species, yet identifying specific evolutionary changes remains challenging. Analysis of single-cell developmental transcriptomes from multiple species provides a powerful framework for unbiased identification of evolutionary changes in developmental mechanisms. Here, we leverage a “natural experiment” in developmental evolution in sea urchins, where a major life history switch recently evolved in the lineage leading toHeliocidaris erythrogramma, precipitating extensive changes in early development. Comparative analyses of scRNA-seq developmental time courses fromH. erythrogrammaandLytechinus variegatus(representing the derived and ancestral states respectively) reveals numerous evolutionary changes in embryonic patterning. The earliest cell fate specification events, and the primary signaling center are co-localized in the ancestral dGRN but remarkably, inH. erythrogrammathey are spatially and temporally separate. Fate specification and differentiation are delayed in most embryonic cell lineages, although in some cases, these processes are conserved or even accelerated. Comparative analysis of regulator-target gene co-expression is consistent with many specific interactions being preserved but delayed inH. erythrogramma, while some otherwise widely conserved interactions have likely been lost. Finally, specific patterning events are directly correlated with evolutionary changes in larval morphology, suggesting that they are directly tied to the life history shift. Together, these findings demonstrate that comparative scRNA-seq developmental time courses can reveal a diverse set of evolutionary changes in embryonic patterning and provide an efficient way to identify likely candidate regulatory interactions for subsequent experimental validation.
Mpf1 is a novel factor that affects the dual distribution of tail-anchored proteins between mitochondria and peroxisomes
Authors: Aravindan Nitya , Vitali Daniela G. , Oberst Jessica , Zalckvar Einat , Schuldiner Maya , Rapaport Doron 
Published: May 2024

AbstractOver half of cellular proteins must target upon their translation to distinct cellular compartments to function. Whereas considerable progress has been made in our understanding of targeting to individual organelles, we know truly little about how proteins distribute their targeting between two, or more, destinations – a process called dual/multiple targeting. In this study, we shine mechanistic insight into the process of dual targeting of proteins between the yeast mitochondria and peroxisomes. We performed a high throughput systematic microscopy screen in which we visualized the location of the model tail-anchored (TA) proteins Fis1 and Gem1 on the background of mutants in all yeast genes. This screen identified three proteins, whose absence resulted in a higher portion of the TA proteins in peroxisomes: the two paralogues Tom70, Tom71, as well as the uncharacterized geneYNL144Cthat we renamedmitochondriaperoxisomes factor 1 (Mpf1). We characterized Mpf1 to be an unstable protein that associated with the cytosolic face of the mitochondrial outer membrane. Furthermore, our study uncovers a unique contribution of Tom71 for the regulation of the dual targeting and reveals a link betweenTOM70/71and the quantity of transcripts ofMPF1. Collectively, our study revealed, for the first-time, factors that influence the dual targeting of proteins between mitochondria and peroxisomes.
Implementing high-throughput insect barcoding in microbiome studies: impact of non-destructive DNA extraction on microbiome reconstruction
Authors: Andriienko Veronika , Buczek Mateusz , Meier Rudolf , Srivathsan Amrita , Łukasik Piotr , Kolasa Michał R. 
Published: May 2024

AbstractBackgroundSymbiotic relationships with diverse microorganisms are crucial for many aspects of insect biology. However, while our understanding of insect taxonomic diversity and the distribution of insect species in natural communities is limited, we know much less about their microbiota. In the era of rapid biodiversity declines, as researchers increasingly turn towards DNA-based monitoring, developing and broadly implementing approaches for high-throughput and cost-effective characterization of both insect and insect-associated microbial diversity is essential. We need to verify whether approaches such as high-throughput barcoding, a powerful tool for identifying wild insects, would permit subsequent microbiota reconstruction in these specimens.MethodsHigh-throughput barcoding (“megabarcoding”) methods often rely on non-destructive approaches for obtaining template DNA for PCR amplification by leaching DNA out of insect specimens using alkaline buffers such as HotSHOT. This study investigated the impact of HotSHOT on microbial abundance estimates and the reconstructed bacterial community profiles. We addressed this question by comparing quantitative 16S rRNA amplicon sequencing data for HotSHOT-treated or untreated specimens of 16 insect species representing six orders and selected based on the expectation of limited variation among individuals.ResultsWe find that in 13 species, the treatment significantly reduced microbial abundance estimates, corresponding to an estimated 15-fold decrease in amplifiable 16S rRNA template on average. On the other hand, HotSHOT pre-treatment had a limited effect on microbial community composition. The reconstructed presence of abundant bacteria with known significant effects was not affected. On the other hand, we observed changes in the presence of low-abundance microbes, those close to the reliable detection threshold. Alpha and beta diversity analyses showed compositional differences in only a few species.ConclusionOur results indicate that HotSHOT pre-treated specimens remain suitable for microbial community composition reconstruction, even if abundance may be hard to estimate. These results indicate that we can cost-effectively combine barcoding with the study of microbiota across wild insect communities. Thus, the voucher specimens obtained using megabarcoding studies targeted at characterizing insect communities can be used for microbiome characterizations. This can substantially aid in speeding up the accumulation of knowledge on the microbiomes of abundant and hyperdiverse insect species.
A metabotropic glutamate receptor agonist enhances visual signal fidelity in a mouse model of retinitis pigmentosa
Authors: Li Xiaoyi , Sedlacek Miloslav , Nath Amurta , Szatko Klaudia P. , Grimes William N. , Diamond Jeffrey S. 
Published: May 2024

AbstractMany inherited retinal diseases target photoreceptors, which transduce light into a neural signal that is processed by the downstream visual system. As photoreceptors degenerate, physiological and morphological changes to retinal synapses and circuitry reduce sensitivity and increase noise, degrading visual signal fidelity. Here, we pharmacologically targeted the first synapse in the retina in an effort to reduce circuit noise without sacrificing visual sensitivity. We tested a strategy to partially replace the neurotransmitter lost when photoreceptors die with an agonist of receptors that ON bipolars cells use to detect glutamate released from photoreceptors. Inrd10mice, which express a photoreceptor mutation that causes retinitis pigmentosa (RP), we found that a low dose of the mGluR6 agonist L-2-amino-4-phosphonobutyric acid (L-AP4) reduced pathological noise induced by photoreceptor degeneration. After makingin vivoelectroretinogram recordings inrd10mice to characterize the developmental time course of visual signal degeneration, we examined effects of L-AP4 on sensitivity and circuit noise by recordingin vitrolight-evoked responses from individual retinal ganglion cells (RGCs). L-AP4 decreased circuit noise evident in RGC recordings without significantly reducing response amplitudes, an effect that persisted over the entire time course of rod photoreceptor degeneration. Subsequentin vitrorecordings from rod bipolar cells (RBCs) showed that RBCs are more depolarized inrd10retinas, likely contributing to downstream circuit noise and reduced synaptic gain, both of which appear to be ameliorated by hyperpolarizing RBCs with L-AP4. These beneficial effects may reduce pathological circuit remodeling and preserve the efficacy of therapies designed to restore vision.Significance StatementRetinitis Pigmentosa (RP) is an inherited degenerative disease that affects more than two million people worldwide. RP patients first lose peripheral and low-light vision due to the progressive death of their highly sensitive rod photoreceptors. Photoreceptor degeneration induces pathological noise within the retinal circuit, leading to dramatic structural changes that may hamper therapies to restore visual sensitivity. We discovered a pharmacological treatment that reduces pathological activity in a mouse model of RP without diminishing signaling in surviving circuitry. Partially replacing the neurotransmitter lost when photoreceptors die reduced noise in the retinal circuit without eliminating light sensitivity. This approach could limit the impact of the disease on retinal neurons and preserve the efficacy of subsequent restorative therapies.
Redox control of the deubiquitinating enzyme Ubp2 regulates translation during stress
Authors: Santos Clara M. , Cizubu Blanche K. , Okonkwo Dinachi , Chen Chia-Yu , Maske Natori , Snyder Nathan A. , Simoes Vanessa , Washington Erica J. , Silva Gustavo M. 
Published: May 2024

AbstractProtein ubiquitination is essential to govern cell’s ability to cope with harmful environments by regulating many aspects of protein dynamics from synthesis to degradation. As important as the ubiquitination process, the reversal of ubiquitin chains mediated by deubiquitinating enzymes (DUBs) is critical for proper recovery from stress and re-establishment of proteostasis. Although it is known that ribosomes are decorated with K63-linked polyubiquitin (K63-ub) chains that control protein synthesis under stress, the mechanisms by which these ubiquitin chains are reversed and regulate proteostasis during stress recovery are still illusive. Here, we showed in budding yeast that the DUB Ubp2 is redox regulated during oxidative stress in a reversible manner, which determines the levels of K63-ub chains present on ribosomes. We also demonstrate that Ubp2 is a processive enzyme whose activity is modulated by a series of repeated domains and the formation of important disulfide bonds. By combining, cellular, biochemical, and proteomics analyses, we showed that Ubp2 is crucial for restoring translation after stress cessation, indicating an important role in determining cellular response to oxidative stress. Our work demonstrates a novel role for Ubp2, revealing that a range of signaling pathways can be controlled by redox regulation of DUB activity in eukaryotes, which in turn will define cellular states of health and diseases.