bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparing alpha-synuclein-interactomes between multiple systems atrophy and Parkinson’s disease reveals unique and shared pathological features
Authors: Choi S.G. , Tittle T. , Barot R , Betts D. , Gallagher J. , Kordower J.H. , Chu Y. , Killinger B.A. 
Published: September 2024

AbstractIntroductionPrimary synucleinopathies, such as Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are neurodegenerative disorders with some shared clinical and pathological features. Aggregates of alpha-synuclein (αsyn) phosphorylated at serine 129 (PSER129) are the hallmark of synucleinopathies, which for PD/DLB are found predominantly in neurons (Neuronal cytoplasmic inclusions “NCIs”), but for MSA, aggregates are primarily found in oligodendroglia (Glial cytoplasmic inclusions “GCIs”). It remains unclear if the distinct pathological presentation of PD/DLB and MSA are manifestations of distinct or shared pathological processes. We hypothesize that the distinct synucleinopathies MSA and PD/DLB share common molecular features.MethodsUsing the in-situ proximity labeling technique biotinylation by antibody recognition (BAR), we compare aggregated αsyn-interactomes (BAR-PSER129) and total αsyn-interactomes (BAR-MJFR1) between MSA (n=5) and PD/DLB (n=10) in forebrain and midbrain structures.ResultsFor BAR-PSER129 and BAR-MJFR1 captures, αsyn was the most significantly enriched protein in PD/DLB and MSA. In PD/DLB, BAR-PSER129 identified 194 αsyn-aggregate-interacting proteins, while BAR-MJFR1 identified 245 αsyn interacting proteins. In contrast, in the MSA brain, only 38 and 175 proteins were identified for each capture, respectively. When comparing MSA and PD/DLB, a high overlap (59.5%) was observed between BAR-MJFR1 captured proteins, whereas less overlap (14.4%) was observed for BAR-PSER129. Direct comparison between MSA and PD/DLB revealed 79 PD/DLB-associated proteins and only three MSA-associated proteins (CBR1, CRYAB, and GFAP). Pathway enrichment analysis revealed PD/DLB interactions were dominated by vesicle/SNARE-associated pathways, in contrast to MSA, which strongly enriched for metabolic/catabolic, iron, and cellular oxidant detoxification pathways. A subnetwork of cytosolic antioxidant enzymes called peroxiredoxins drove cellular detoxification pathways in MSA. A common network of 26 proteins, including neuronal-specific proteins (e.g., SNYGR3) with HSPA8 at the core, was shared between MSA and DLB/PD. Extracellular exosome pathways were universally enriched regardless of disease or BAR target protein.ConclusionSynucleinopathies have divergent and convergent αsyn-aggregate interactions, indicating unique and shared pathogenic mechanisms. MSA uniquely involves oxidant detoxification processes in glial cells, while vesicular processes in neurons dominate PD/DLB. Shared interactions, specifically SNYGR3 (i.e., a neuronal protein), between MSA and PD/DLB suggest neuronal axons origin for both diseases. In conclusion, we provide αsyn aggregates protein interaction maps for two distinct synucleinopathies.
Vocal Call Locator Benchmark (VCL) for localizing rodent vocalizations from multi-channel audio
Authors: Peterson Ralph E , Tanelus Aramis , Ick Christopher , Mimica Bartul , Francis Niegil , Ivan Violet J , Choudhri Aman , Falkner Annegret L , Murthy Mala , Schneider David M , Sanes Dan H , Williams Alex H 
Published: September 2024

AbstractUnderstanding the behavioral and neural dynamics of social interactions is a goal of contemporary neuroscience. Many machine learning methods have emerged in recent years to make sense of complex video and neurophysiological data that result from these experiments. Less focus has been placed on understanding how animals process acoustic information, including social vocalizations. A critical step to bridge this gap is determining the senders and receivers of acoustic information in social interactions. While sound source localization (SSL) is a classic problem in signal processing, existing approaches are limited in their ability to localize animal-generated sounds in standard laboratory environments. Advances in deep learning methods for SSL are likely to help address these limitations, however there are currently no publicly available models, datasets, or benchmarks to systematically evaluate SSL algorithms in the domain of bioacoustics. Here, we present the VCL Benchmark: the first large-scale dataset for benchmarking SSL algorithms in rodents. We acquired synchronized video and multi-channel audio recordings of 767,295 sounds with annotated ground truth sources across 9 conditions. The dataset provides benchmarks which evaluate SSL performance on real data, simulated acoustic data, and a mixture of real and simulated data. We intend for this benchmark to facilitate knowledge transfer between the neuroscience and acoustic machine learning communities, which have had limited overlap.
ERAP1 activity modulates the immunopeptidome but also affects the proteome, metabolism and stress responses in cancer cells
Authors: Nikopaschou Martha , Samiotaki Martina , Stylianaki Ellie-Anna , Król Kamila , Gragera Paula , Raja Aroosha , Aidinis Vassilis , Chroni Angeliki , Fruci Doriana , Panayotou George , Stratikos Efstratios 
Published: September 2024

ABSTRACTEndoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) metabolizes peptides inside the ER and shapes the peptide repertoire available for binding to Major Histocompatibility Complex Class I molecules (MHC-I). Moreover, it may have additional effects on cellular homeostasis, which have not been explored. To address these questions, we used both genetic silencing of ERAP1 expression as well as treatment with a selective allosteric ERAP1 inhibitor to probe changes in the immunopeptidome and proteome of the A375 melanoma cancer cell line. We observed significant immunopeptidome shifts with both methods of functional ERAP1 disruption, which were distinct for each method. Both methods of inhibition led to an enhancement, albeit slight, in tumor cell killing by stimulated human PBMCs and in significant proteomic alterations in pathways related to metabolism and cellular stress. Similar proteomic changes were also observed in the leukemia cell line THP-1. Biochemical analyses suggested that ERAP1 inhibition affected sensitivity to ER stress, reactive oxygen species production and mitochondrial metabolism. Although the proteomics shifts were significant, their potential in shaping immunopeptidome shifts was limited since only 15.8% of differentially presented peptides belonged to proteins with altered expression and only 5.0% of proteins with altered expression were represented in the immunopeptidome shifts. Taken together, our findings suggest that modulation of ERAP1 activity can generate unique immunopeptidomes, mainly due to altered peptide processing in the ER, but also induce changes in the cellular proteome and metabolic state which may have further effects on tumor cells.
Extinction of innate floral preferences in the pollinatorEristalis tenax
Authors: Rajan Deepa , Mishra Aditi , Sharan Maansi , Gharpure Gauri , Olsson Shannon 
Published: September 2024

ABSTRACTInnate behaviors allow solitary animals to complete essential tasks in the absence of social learning. However, we know little about the degree to which ecologically relevant innate preferences can change. The hoverflyEristalis tenax, a solitary generalist pollinator, is an ideal model for studying innate behavior in a naturalistic context because its survival depends on the innate ability to identify flowers. Innate behavior inE. tenaxhas previously been considered inalterable, but we hypothesized thatE. tenaxcan modulate their innate behavior after training in a multimodal sensory context, in contrast to the prior work that employed unimodal sensory cues. To test this, we examined ifE. tenaxcan extinguish an innate proboscis extension response (PER) to a multimodal floral object after undergoing aversive conditioning with quinine, and if flies can acquire PER to an innately unattractive object using sucrose as reinforcement. Finally, we assessed long-term memory retention. Here, we report a complete extinction of the proboscis extension response (PER) to an innately attractive floral object following aversive training.E. tenaxcan also acquire PER to an innately unattractive object after appetitive training. Flies can retain these memories for days after training, and aversive memories last longer than appetitive memories. Our results contrast with literature stating that innate preferences cannot be extinguished inE. tenax. This could be because our study uses multimodal objects instead of the unimodal stimuli used in previous work. Ultimately, these findings improve our understanding of how animals navigate the uncertainties of dynamic objects in the natural world.
Nucleation limited assembly and polarized growth of ade novo-designed allosterically modulatable protein filament
Authors: Shen Hao , Lynch Eric M. , Watson Joseph L. , Wu Kejia , Bai Hua , Sheffler William , Derivery Emmanuel , Kollman Justin , Baker David 
Published: September 2024

AbstractThe design of inducibly assembling protein nanomaterials is an outstanding challenge. Here, we describe the computational design of a protein filament formed from a monomeric subunit which binds a peptide ligand. The cryoEM structure of the micron scale fibers is very close to the computational design model. The ligand acts as a tunable allosteric modulator: while not part of the fiber subunit-subunit interfaces, the assembly of the filament is dependent on ligand addition, with longer peptides having more extensive interaction surfaces with the monomer promoting more rapid growth. Seeded growth and capping experiments reveal that the filaments grow primarily from one end. Oligomers containing 12 copies of the peptide ligand nucleate fiber assembly from monomeric subunit and peptide mixtures at concentrations where assembly occurs very slowly, likely by generating critical local concentrations of monomer in the assembly competent conformation. Following filament assembly, the peptide ligand can be exchanged with free peptide in solution, and it can be readily fused to any functional protein of interest, opening the door to a wide variety of tunable engineered materials.
Spinal neuron diversity scales exponentially with swim-to-limb transformation during frog metamorphosis
Authors: Vijatovic David , Toma Florina Alexandra , Harrington Zoe P. M. , Sommer Christopher , Hauschild Robert , Trevisan Alexandra J. , Chapman Phillip , Julseth Mara J. , Brenner-Morton Susan , Gabitto Mariano I. , Dasen Jeremy S. , Bikoff Jay B. , Sweeney Lora B. 
Published: September 2024

SUMMARYVertebrates exhibit a wide range of motor behaviors, ranging from swimming to complex limb-based movements. Here we take advantage of frog metamorphosis, which captures a swim-to-limb-based movement transformation during the development of a single organism, to explore changes in the underlying spinal circuits. We find that the tadpole spinal cord contains small and largely homogeneous populations of motor neurons (MNs) and V1 interneurons (V1s) at early escape swimming stages. These neuronal populations only modestly increase in number and subtype heterogeneity with the emergence of free swimming. In contrast, during frog metamorphosis and the emergence of limb movement, there is a dramatic expansion of MN and V1 interneuron number and transcriptional heterogeneity, culminating in cohorts of neurons that exhibit striking molecular similarity to mammalian motor circuits. CRISPR/Cas9-mediated gene disruption of the limb MN and V1 determinants FoxP1 and Engrailed-1, respectively, results in severe but selective deficits in tail and limb function. Our work thus demonstrates that neural diversity scales exponentially with increasing behavioral complexity and illustrates striking evolutionary conservation in the molecular organization and function of motor circuits across species.
Premature upregulation of miR-92a’s target RBFOX2 hijacks PTBP splicing and impairs cortical neuronal differentiation
Authors: Weißbach Stephan , Todorov Hristo , Schlichtholz Laura , Mühlbauer Sophia , Zografidou Lea , Soliman Azza , Lor-Zade Sarah , Hartwich Dewi , Strand Dennis , Strand Susanne , Vogel Tanja , Heine Martin , Gerber Susanne , Winter Jennifer 
Published: September 2024

AbstractRBFOX2 is an RNA-binding protein crucial for alternative splicing regulation and implicated in several neurodevelopmental disorders. Here, we show that while RBFOX2 is present only at low levels in neural progenitor cells (NPCs), it is upregulated in differentiating neurons of the mouse embryonic neocortex.In-utero-electroporation-induced overexpression resulted in a cellular phenotype characterized by impaired neuronal migration and differentiation. Genome-wide analysis at E15.5 revealed numerous alternative splicing events associated with a mixed NPC- and neuron-like splicing pattern and a significant deviation from the normal splicing developmental trajectory. Remarkably, prematureRbfox2overexpression induced the inclusion of validated target exons that are otherwise repressed by PTBP2, indicating an antagonistic splicing relationship between these two RNA-binding proteins and highlighting the necessity for strict temporal regulation of their expression during embryonic brain development. Consequently, we showed that the NPC-specific miRNA 92a-3p reduced the expression levels ofRbfox2 in vitro. Furthermore, silencing miR-92a-3pin vivoin the embryonic neocortex led to a significant increase inRbfox2levels. Our results therefore demonstrate that RBFOX2 is a crucial player in the NPC-to-neuron splicing switch. Furthermore, we present a novel post-transcriptional mechanism for controlling RBFOX2 levels during early neuronal differentiation via miR-92a-3p silencing.
Neuralized-like proteins differentially activate Notch ligands
Authors: Airich Alina , Gozlan Oren , Seib Ekaterina , Wilschrey Lena-Sophie , Shaingarten Gittel Leah , Sprinzak David , Klein Thomas 
Published: September 2024

AbstractNotch signalling is a major signalling pathway coordinating cellular processes between neighbouring animal cells. In Drosophila, two ubiquitin ligases, Neuralized (Neur) and Mindbomb1 (Mib1), regulate Notch ligand activation and are essential for development. However, the mammalian orthologs of Neur, Neuralized-like (NEURL) 1 and 2, do not appear to be crucial for development, as double knock-out mice show no developmental defects. Thus, it is unclear if and how NEURL proteins regulate the four mammalian Notch ligands. To address these questions, we examined NEURL proteins’ ability to activate Notch ligands in humanizedDrosophilaand mammalian cell culture. We found that, unlike MIB1, NEURL proteins activate Notch only with a subset of mammalian ligands, which contain a Neuralized binding motif. This motif has the consensus sequence NxxN, present only in Notch ligands DLL1 and JAG1, but not in DLL4 and JAG2. Overall, we show that NEURL proteins activate specific Notch-ligands, suggesting a differential regulatory mechanism of Notch activation in mammals, which can potentially explain the limited role of NEURL proteins in mammalian development and homeostasis.
Bacterial growth under confinement requires transcriptional adaptation to resist metabolite-induced turgor pressure build-up
Authors: Blanc Laure Le , Alric Baptiste , Rollin Romain , Xénard Laura , Finn Laura Ramirez , Goussard Sylvie , Mazenq Laurent , Ingersoll Molly A. , Piel Matthieu , Tinevez Jean-Yves , Delarue Morgan , Duménil Guillaume , Bonazzi Daria 
Published: September 2024

SUMMARYBacterial proliferation often occurs in confined spaces, during biofilm formation, within host cells, or in specific niches during infection, creating mechanical constraints. We investigated how spatial confinement and growth-induced mechanical pressure affect bacterial physiology. Here, we found that, when proliferating in a confining microfluidic-based device with access to nutrients,Escherichia colicells generate forces in the hundreds of kPa range. This pressure decouples growth and division, producing shorter bacteria with higher protein concentrations. This leads to cytoplasmic crowding, which ultimately arrests division and stalls protein synthesis. In this arrested state, the pressure produced by bacteria keeps increasing. A minimal theoretical model of bacterial growth predicts this novel regime of steady pressure increase in the absence of protein production, that we namedoverpressurization. In this regime, the Rcs pathway is activated and that abnormal shapes appear inrcsmutant populations only when they reach the overpressurized state. A uropathogenic strain ofE. colidisplayed the same confined growth phenotypesin vitroand requirement for Rcs in a mice model of urinary tract infection, suggesting that these pressurized regimes are relevant to understand the physiopathology of bacterial infections.
A characterization of mitotic and centrosomal defects in a continuum model of Breast Cancer
Authors: Santos Alexsandro dos , Diorio Caroline , Durocher Francine , Elowe Sabine 
Published: September 2024

ABSTRACTErrors in mitosis can contribute to aneuploidy and CIN and play a pivotal role in cancer. So the identification of altered mitotic regulators can contribute to the understanding of the development and progression of breast cancer. In the present study we used anin vitromodel of disease progression (the MCF10A series of BC continuum) and analyzed the errors of chromosome segregation that occur during the progression of the disease. Our findings indicated that the MCF10A series exhibited several abnormalities in chromosome segregation and its frequency increased with the disease progression. These errors included anaphase lagging chromosomes, micronuclei, nuclear buds, nucleoplasmic bridges, errors of chromosome alignment, and centrosome loss/amplification. Moreover, the presence of centrosome amplification disrupted the proper orientation of the mitotic spindle, resulting in the generation asymmetrical cell lines and aneuploidy in the MCF10A series. Hyper stable kinetochore-microtubule (kt-MT) attachment was also found in premalignant, preinvasive, and invasive cell lines, which can also explain the presence of errors of chromosome alignment. The human transcriptome array also determined possible negative regulators of ciliogenesis that can explain the mechanism of chromosome missegregation that lead to CIN found in the MCF10A series. Collectively, these findings highlight the importance of mitotic defects in the progression of breast cancer.
Human medial pulvinar is involved in face and tactile processing and dynamically adjusts its cortical connectivity based on ongoing stimulation
Authors: Gaudet-Trafit M. , Froesel M. , Dali S. , Lamberton F. , Ben Hamed S. 
Published: September 2024

ABSTRACTOptimal processing of our surrounding environment relies on our ability to detect and integrate external information through multiple sensory modalities to build a coherent representation of the world. Interactions between cortical and subcortical structures contribute to this process. In this context, there is growing evidence that the pulvinar plays a crucial role in visual and face processing. In contrast, its role in auditory, voice and tactile processing has been poorly investigated. Here, we use fMRI localizer tasks to describe pulvinar functional organization and functional connectivity with the brain during face, voice and tactile processing. We reproduce the activation of the ventral part of the medial pulvinar in face perception and we describe an increased pulvinar connectivity with face processing areas and a decreased connectivity with low level visual areas during face processing. In addition, we describe activations of the medial pulvinar during air-puff face, hands and feet tactile stimulations and changes in pulvino-cortical connectivity as a function of which body part is being stimulated. No activations are observed during either voice or non-voice stimulations. Overall, this supports a role of medial pulvinar in multisensory processing and the modulation of cortical areas as a function of the sensory context.
SATAY-Based Chemogenomic Screening uncovers Antifungal Resistance Mechanisms and Key Determinants of ATI-2307 and Chitosan Sensitivity
Authors: Karadzas Matthew T. , Michel Agnès H. , Mosbach Andreas , Giannakopoulos George , McGettigan Ruairi , Scalliet Gabriel , Kornmann Benoît 
Published: September 2024

AbstractMultidrug-resistant fungal pathogens are a serious threat to public health and global food security. Mitigation requires the discovery of antifungal compounds with novel modes of action, along with a comprehensive understanding of the molecular mechanisms governing antifungal resistance. Here, we apply SAturated Transposon Analysis in Yeast (SATAY), a powerful transposon sequencing method inSaccharomyces cerevisiae, to uncover loss- and gain-of-function mutations conferring resistance to 20 different antifungal compounds. These screens identify a diverse array of novel resistance mechanisms and multiple modes of action. SATAY is performed in drug-sensitive strains to generate chemogenomic profiles for compounds that lack activity against conventional laboratory strains. This study therefore provides a significant resource for exploring cellular responses to chemical stresses. We discover that the natural antifungal Chitosan electrostatically interacts with cell wall mannosylphosphate, and that the transporter Hol1 concentrates the novel antifungal ATI-2307 within yeast. This latter finding presents an avenue for drug design initiatives, but also unveils a straightforward evolutionary path to ATI-2307 resistance with minimal fitness cost.
A role for acetylcholine in reinforcement learning and decision making under uncertainty
Authors: Kurtenbach Hannah , Froböse Monja Isabel , Ort Eduard , Bahners Bahne Hendrik , Hirschmann Jan , Butz Markus , Schnitzler Alfons , Jocham Gerhard 
Published: September 2024

AbstractThe neuromodulator acetylcholine has been suggested to govern learning under uncertainty. Here, we investigated the role of muscarinic receptors in reward-guided learning and decision making under different degrees of uncertainty. We administered the muscarinic M1 antagonist biperiden (4 mg) to healthy male participants (n = 43) in a within-subjects, placebo-controlled design. Participants performed two tasks that both involved choices between options characterized by two attributes, reward probability and magnitude. In the gambling task, both attributes were explicitly provided, whereas in the learning task, reward probabilities had to be inferred from past experience. In addition, uncertainty was manipulated within the learning task by inclusion of a stable phase with fixed reward contingencies, and a volatile phase with frequent contingency reversals. We show that biperiden did not affect decision making in the gambling task, where no learning was required. However, in the learning task, biperiden reduced the sensitivity to the learnt reward probabilities. Notably, this was primarily driven by choices under higher uncertainty in the volatile phase. Using reinforcement learning models, we reveal that the change in behaviour was caused by noisier estimates of probabilities resulting from maladaptively increased learning rates under biperiden. Together, these findings suggest that muscarinic acetylcholine transmission is involved in controlling learning in highly uncertain contexts, when the demand for carefully calibrated adjustments is highest.