bluuebunny/crossref_metadata_2025_split huggingface dataset:
Probe-dependent Proximity Profiling (ProPPr) Uncovers Similarities and Differences in Phospho-Tau-Associated Proteomes Between Tauopathies
Authors: Morderer Dmytro , Wren Melissa C. , Liu Feilin , Kouri Naomi , Maistrenko Anastasiia , Khalil Bilal , Pobitzer Nora , Salemi Michelle , Phinney Brett S. , Dickson Dennis W. , Murray Melissa E. , Rossoll Wilfried 
Published: March 2024

AbstractTauopathies represent a diverse group of neurodegenerative disorders characterized by the abnormal aggregation of the microtubule-associated protein tau. Despite extensive research, the precise mechanisms underlying the complexity of different types of tau pathology remain incompletely understood. Here we describe an approach for proteomic profiling of aggregate-associated proteomes on slides with formalin-fixed, paraffin-embedded (FFPE) tissue that utilizes proximity labelling upon high preservation of aggregate morphology, which permits the profiling of pathological aggregates regardless of their size. To comprehensively investigate the common and unique protein interactors associated with the variety of tau lesions present across different human tauopathies, Alzheimer’s disease (AD), corticobasal degeneration (CBD), Pick’s disease (PiD), and progressive supranuclear palsy (PSP), were selected to represent the major tauopathy diseases. Implementation of our widely applicable Probe-dependent Proximity Profiling (ProPPr) strategy, using the AT8 antibody, permitted identification and quantification of proteins associated with phospho-tau lesions in well-characterized human post-mortem tissue. The analysis revealed both common and disease-specific proteins associated with phospho-tau aggregates, highlighting potential targets for therapeutic intervention and biomarker development. Candidate validation through high-resolution co-immunofluorescence of distinct aggregates across disease and control cases, confirmed the association of retromer complex protein VPS35 with phospho-tau lesions across the studied tauopathies. Furthermore, we discovered disease-specific associations of proteins including ferritin light chain (FTL) and the neuropeptide precursor VGF within distinct pathological lesions. Notably, examination of FTL-positive microglia in CBD astrocytic plaques indicate a potential role for microglial involvement in the pathogenesis of these tau lesions. Our findings provide valuable insights into the proteomic landscape of tauopathies, shedding light on the molecular mechanisms underlying tau pathology. This first comprehensive characterization of tau-associated proteomes across different tauopathies enhances our understanding of disease heterogeneity and provides a resource for future functional investigation, as well as development of targeted therapies and diagnostic biomarkers.
Identification and characterization of nanobodies acting as molecular chaperones for glucocerebrosidase through a novel allosteric mechanism
Authors: Maso Thomas Dal , Sinisgalli Chiara , Zilio Gianluca , Tessari Isabella , Pardon Els , Steyaert Jan , Ballet Steven , Greggio Elisa , Versées Wim , Plotegher Nicoletta 
Published: March 2024

AbstractThe enzyme glucocerebrosidase (GCase) catalyses the hydrolysis of glucosylceramide to glucose and ceramide within lysosomes. Homozygous or compound heterozygous mutations in the GCase-sencodingGBA1gene cause the lysosomal storage disorder Gaucher disease, while heterozygous mutations are the most frequent genetic risk factor for Parkinson’s disease. These mutations commonly affect GCase stability, trafficking or activity. Here, we report the development and characterization of nanobodies (Nbs) targeting and acting as chaperones for GCase. We identified several Nb families that bind with nanomolar affinity to GCase. Based on biochemical characterization, we grouped the Nbs in two classes: Nbs that improve the activity of the enzyme and Nbs that increase GCase stabilityin vitro. A selection of the most promising Nbs was shown to improve GCase function in cell models and positively impact the activity of the N370S mutant GCase. These results lay the foundation for the development of new therapeutic routes.
Immunosuppression in the prostate tumor microenvironment is tied to androgen deprivation therapy-resistant club-like cells
Authors: Kiviaho Antti , Eerola Sini K. , Kallio Heini M.L. , Andersen Maria K. , Spotbeen Xander , Giesen Alexander , Parker Charles T.A. , Taavitsainen Sinja , Hantula Olli , Marttinen Mikael , Hermelo Ismaïl , Ismail Mazlina , Midtbust Elise , Wess Maximilian , Devlies Wout , Sharma Abhibhav , Krossa Sebastian , Häkkinen Tomi , Afyounian Ebrahim , Kesseli Juha , Tolonen Teemu , Tammela Teuvo L.J. , Viset Trond , Størkersen Øystein , Giskeødegård Guro F. , Rye Morten B. , Murtola Teemu , Erickson Andrew , Latonen Leena , Bova G. Steven , Mills Ian G. , Joniau Steven , Swinnen Johannes V. , Voet Thierry , Mirtti Tuomas , Attard Gerhardt , Claessens Frank , Visakorpi Tapio , Rautajoki Kirsi J. , Tessem May-Britt , Urbanucci Alfonso , Nykter Matti 
Published: March 2024

AbstractProstate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 110 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells partake in inducing myeloid inflammation previously associated with androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting.
Spermidine/spermine N1-acetyltransferase controls tissue-specific regulatory T cell function in chronic inflammation
Authors: Neuwirth Teresa , Malzl Daniel , Knapp Katja , Tsokkou Panagiota , Kleissl Lisa , Redl Anna , Freystätter Christian , Marella Nara , Kutschat Ana P. , Ponweiser Elisabeth , Haschemi Arvand , Seruggia Davide , Menche Jörg , Wagner Erwin F. , Stary Georg 
Published: March 2024

SummaryRegulatory T cells (Tregs) are a critical immune component guarding against excessive inflammatory responses. During chronic inflammation, Tregsfail to control effector T cell responses. The causes of Tregdysfunction in these diseases are poorly characterized and therapies are aimed at blocking aberrant effector responses rather than rescuing Tregfunction. Here we utilized single-cell RNA sequencing data from patients suffering from chronic skin and colon inflammation to uncoverSAT1, the gene encoding spermidine/spermine N1-acetyltransferase (SSAT), as a novel marker and driver of skin-specific Tregdysfunction during TH17-mediated inflammation. TregsexpressingSAT1exhibit a tissue-specific inflammation signature and show a proinflammatory effector-like profile. In CRISPRa on healthy human skin-derived Tregsincreased expression ofSAT1leads to a loss of suppressive function and a switch to a TH17-like phenotype. This phenotype is induced by co-receptor expression on keratinocytes exposed to a TH17 microenvironment. Finally, the potential therapeutic impact of targeting SSAT was demonstrated in a mouse model of skin inflammation by inhibiting SSAT pharmacologically, which rescued Tregnumber and function in the skin and systemically. Together, these data show thatSAT1expression has severe functional consequences on Tregsand provides a novel target to treat chronic inflammatory skin disease.
Mutational synergy withCREBBPloss in lymphomagenesis identified through forward insertional mutagenesis in a new DLBCL mouse model
Authors: Sakakini Nathalie , Straver Roy , Azazi Dhoyazan M. A , Horton Sarah J. , Asby Ryan , Richardson Simon E. , Madrigal Pedro , Soilleux Elizabeth J , Bashford-Rogers Rachael , de Ridder Jeroen , Huntly Brian J. P 
Published: March 2024

AbstractLoss-of-function mutations in the gene encoding the acetyltransferase CREBBP have been reported in numerous cancers but are particularly frequent in lymphoid malignancies. However, the functional significance of CREBBP loss in transformation and disease progression, most likely through cooperation with secondary genetic hits, has not yet been fully unravelled. Similarly, the contribution of the initial cell population sustaining CREBBP loss in the course of disease remains elusive. Here, we developed a new lymphoma mouse model integratingCrebbploss at various stages of B cell development with a transposon-based insertional mutagenesis system. We demonstrated thatCrebbploss from the HSPC compartment resulted in an aggressive DLBCL-like disease, recapitulating well-characterised histological and molecular features of the human disease, as well as the recently described enhanced CD24 expression. More importantly, we identified candidate genes functionally equivalent to patient mutated genes. Those genes, mainly related to B cell development and cellular signalling, may represent novel therapeutic targets. Overall, this new model provides a powerful resource in which to conduct future mechanistic and therapeutic studies.
Metal fluorides - multi-functional tools for the study of phosphoryl transfer enzymes
Authors: Pellegrini Erika , Juyoux Pauline , Velsen Jill von , Baxter Nicola J. , Dannatt Hugh R. W. , Yi Jin , Cliff Matthew J. , Waltho Jonathan P. , Bowler Matthew W. 
Published: March 2024

SummaryEnzymes facilitating the transfer of phosphate groups constitute the most extensive protein group across all kingdoms of life, making up approximately 10% of the proteins found in the human genome. Understanding the mechanisms by which enzymes catalyse these reactions is essential in characterising the processes they regulate. Metal fluorides can be used as multifunctional tools for the study of these enzymes. These ionic species bear the same charge as phosphate and the transferring phosphoryl group and, in addition, allow the enzyme to be trapped in catalytically important states with spectroscopically sensitive atoms interacting directly with active site residues. The ionic nature of these phosphate surrogates also allows their removal and replacement with other analogues. Here, we describe the best practices to obtain these complexes, their use in NMR, X-ray crystallography, cryoEM and SAXS and describe a new metal fluoride, scandium tetrafluoride, which has significant anomalous signal with soft X-rays.Highlights⍰Enzymes that catalyse phosphoryl transfer are the largest family of enzymes and are involved in the storage and transmission of genetic information, energy transfer, signalling and cellular differentiation⍰Metal fluorides form a comprehensive tool kit to study the mechanisms of these enzymes by stabilizing the active conformation; mimicking both the transition state and ground state; and placing spectroscopically sensitive atoms into the active site⍰A guide is presented to the optimal formation of these complexes and their use in a wide variety of techniques in structural biology
Theoretical insights into rotary mechanism of MotAB in the bacterial flagellar motor
Authors: Kubo Shintaroh , Okada Yasushi , Takada Shoji 
Published: March 2024

AbstractMany bacteria enable locomotion by rotating their flagellum. It has been suggested that this rotation is realized by the rotary motion of the stator unit, MotAB, which is driven by proton transfer across the membrane. Recent cryo-electron microscopy studies have revealed a 5:2 MotAB configuration, in which a MotB dimer is encircled by a ring-shaped MotA pentamer. While the structure implicates the rotary motion of the MotA wheel around the MotB axle, the molecular mechanisms of rotary motion and how they are coupled with proton transfer across the membrane remain elusive. In this study, we built a structure-based computational model forCampylobacter jejuniMotAB, conducted comprehensive protonation state-dependent molecular dynamics simulations, and revealed a plausible proton-transfer coupled rotation pathway. The model assumes rotation-dependent proton transfer, in which proton uptake from the periplasmic side to the conserved aspartic acid in MotB is followed by proton hopping to the MotA proton-carrying site, followed by proton export to the cytoplasm. We suggest that, by maintaining two of the proton-carrying sites of MotA in the deprotonated state, the MotA pentamer robustly rotates by ∼36° per proton transfer across the membrane. Our results provide a structure-based mechanistic model of the rotary motion of MotAB in bacterial flagellar motors and provide insights into various ion-driven rotary molecular motors.Significance StatementThis study aims to elucidate the mechanism by which bacteria move by rotating their flagella. The driving force for flagellar rotation is predicted to be driven by protons passing through the transmembrane protein MotAB, but the actual rotation mechanism has not yet been elucidated. Using advanced computational modeling and molecular dynamics simulations, we have elucidated the detailed processes by which proton translocation achieves the rotation of the bacterial flagellar motor. This work not only sheds light on the fundamental mechanisms of bacterial motility but also provides a framework for understanding similar ion-driven rotation mechanisms in other biological systems, potentially paving the way for new bioinspired technologies.
Identifying immune signatures of common exposures through co-occurrence of T-cell receptors in tens of thousands of donors
Authors: May Damon H. , Woodhouse Steven , Zahid H. Jabran , Elyanow Rebecca , Doroschak Kathryn , Noakes Matthew T. , Taniguchi Ruth , Yang Zheng , Grino John R. , Byron Rachel , Oaks Jamie , Sherwood Anna , Greissl Julia , Chen-Harris Haiyin , Howie Bryan , Robins Harlan S. 
Published: March 2024

ABSTRACTMemory T cells are records of clonal expansion from prior immune exposures, such as infections, vaccines and chronic diseases like cancer. A subset of the receptors of these expanded T cells in a typical immune repertoire are highly public, i.e., present in many individuals exposed to the same exposure. For the most part, the exposures associated with these public T cells are unknown.To identify public T-cell receptor signatures of immune exposures, we mined the immunosequencing repertoires of tens of thousands of donors to define clusters of co-occurring T cells. We first built co-occurrence clusters of T cells responding to antigens presented by the same Human Leukocyte Antigen (HLA) and then combined those clusters across HLAs. Each cross-HLA cluster putatively represents the public T-cell signature of a single prevalent exposure.Using repertoires from donors with known serological status for 7 prevalent exposures (HSV-1, HSV-2, EBV, Parvovirus,Toxoplasma gondii, Cytomegalovirus and SARS-CoV-2), we identified a single T-cell cluster strongly associated with each exposure and used it to construct a highly sensitive and specific diagnostic model for the exposure.These T-cell clusters constitute the public immune responses to prevalent exposures, 7 known and many others unknown. By learning the exposure associations for more T-cell clusters, this approach could be used to derive a ledger of a person’s past and present immune exposures.
The white matter fiber tract deforms most in the perpendicular direction duringin vivovolunteer impacts
Authors: Zhou Zhou , Olsson Christoffer , Gasser T. Christian , Li Xiaogai , Kleiven Svein 
Published: March 2024

AbstractWhite matter (WM) tract-related strains are increasingly used to quantify brain mechanical responses, but their dynamics in live human brains duringin vivoimpact conditions remain largely unknown. Existing research primarily looked into the normal strain along the WM fiber tracts (i.e., tract-oriented normal strain), but it is rarely the case that the fiber tract only endures tract-oriented normal strain during impacts. In this study, we aim to extend thein vivomeasurement of WM fiber deformation by quantifying the normal strain perpendicular to the fiber tract (i.e., tract-perpendicular normal strain) and the shear strain along and perpendicular to the fiber tract (i.e., tract-oriented shear strain and tract-perpendicular shear strain, respectively). To achieve this, we combine the three-dimensional strain tensor from the tagged magnetic resonance imaging (tMRI) with the diffusion tensor imaging (DTI) from an open-access dataset, including 44 volunteer impacts under two head loading modes, i.e., neck rotations (N = 30) and neck extensions (N = 14). The strain tensor is rotated to the coordinate system with one axis aligned with DTI-revealed fiber orientation and then four tract-related strain measures are calculated. The results show that tract-perpendicular normal strain peaks are the largest among the four strain types (p< 0.05, Friedman’s test). The distribution of tract-related strains is affected by the head loading mode, of which laterally symmetric patterns with respect to the midsagittal plane are noted under neck extensions, but not under neck rotations. Our study presents a comprehensivein vivostrain quantification towards a multifaceted understanding of WM dynamics. We find the WM fiber tract deforms most in the perpendicular direction, illuminating new fundamentals of brain mechanics. The reported strain images can be used to evaluate the fidelity of computational head models, especially those intended to predict fiber deformation under non-injurious conditions.
The respiratory cycle modulates distinct dynamics of affective and perceptual decision-making
Authors: Brændholt Malthe , Nikolova Niia , Vejlø Melina , Banellis Leah , Fardo Francesca , Kluger Daniel S. , Allen Micah 
Published: March 2024

AbstractRespiratory rhythms play a critical role not only in homeostatic survival, but also in modulating other non-interoceptive perceptual and affective processes. Recent evidence from both human and rodent models indicates that neural and behavioural oscillations are influenced by respiratory state as breathing cycles from inspiration to expiration. To explore the mechanisms behind these effects, we carried out a psychophysical experiment where 41 participants categorised dot motion and facial emotion stimuli in a standardised discrimination task. When comparing behaviour across respiratory states, we found that inspiration accelerated responses in both domains. We applied a hierarchical evidence accumulation model to determine which aspects of the latent decision process best explained this acceleration. Computational modelling showed that inspiration reduced evidential decision boundaries, such that participants prioritised speed over accuracy in the motion task. In contrast, inspiration shifted the starting point of affective evidence accumulation, inducing a bias towards categorising facial expressions as more positive. These findings provide a novel computational account of how respiratory rhythms modulate distinct aspects of perceptual and affective decision-dynamics.
Variations of autonomic arousal mediate the reportability of mind-blanking occurrences
Authors: Alexandros Boulakis Paradeisios , John Simos Nicholas , Stefania Zoi , Sepehr Mortaheb , Christina Schmidt , Federico Raimondo , Athena Demertzi 
Published: March 2024

AbstractMind-blanking (MB) is the inability to report mental events during unconstraint thinking. Previous work shows that MB is linked to decreased levels of cortical arousal, indicating dominance of cerebral mechanisms when reporting mental states. What remains inconclusive is whether MB can also ensue from autonomic arousal manipulations, pointing to the implication of peripheral physiology to mental events. Using experience-sampling, neural, and physiological measurements in 26 participants, we first show that MB was reported more frequently in low arousal conditions, elicited by sleep deprivation. Also, there was partial evidence for a higher number of MB reports in high arousal conditions, elicited by intense physical exercise. Transition probabilities revealed that, after sleep deprivation, mind-wandering was more likely to be followed by MB and less likely to be followed by more mind-wandering reports. Using classification schemes, we show higher performance of a balanced random forest classifier trained on both neural and physiological markers in comparison to performance when solely neural or physiological were used. Collectively, we show that both cortical and autonomic arousal affect MB report occurrences. Our results establish that MB is supported by combined brain-body configurations, and, by linking mental and physiological states they pave the way for novel, embodied accounts of spontaneous thinking.
TheDrosophilaRNA binding protein Hrp48 binds a specific RNA sequence of themsl-2mRNA 3’ UTR to regulate translation
Authors: Lomoschitz Andrea , Meyer Julia , Guitart Tanit , Krepl Miroslav , Lapouge Karine , Hayn Clara , Schweimer Kristian , Simon Bernd , Šponer Jiří , Gebauer Fátima , Hennig Janosch 
Published: March 2024

AbstractRepression ofmsl-2mRNA translation is essential for viability ofDrosophila melanogasterfemales to prevent hypertranscription of both X chromosomes. This translational control event is coordinated by the female-specific protein Sex-lethal (Sxl) which recruits the RNA binding proteins Unr and Hrp48 to the 3’ untranslated region (UTR) of themsl-2transcript and represses translation initiation. The mechanism exerted by Hrp48 during translation repression and its interaction withmsl-2are not well understood. Here we investigate the RNA binding specificity and affinity of the tandem RNA recognition motifs of Hrp48. Using NMR spectroscopy, molecular dynamics simulations and isothermal titration calorimetry, we identified the exact region ofmsl-23’ UTR recognized by Hrp48. Additional biophysical experiments and translation assays give further insights into complex formation of Hrp48, Unr, Sxl and RNA. Our results show that Hrp48 binds independent of Sxl and Unr downstream of the E and F binding sites of Sxl and Unr tomsl-2.
Unravelling the architecture of Major Histocompatibility Complex class II haplotypes in rhesus macaques
Authors: de Groot Nanine , van der Wiel Marit , Le Ngoc Giang , de Groot Natasja G. , Bruijnesteijn Jesse , Bontrop Ronald E. 
Published: March 2024

AbstractThe regions in the genome that encode components of the immune system are often featured by polymorphism, copy number variation and segmental duplications. There is a need to thoroughly characterize these complex regions to gain insight into the impact of genomic diversity on health and disease. Here we resolve the organization of complete major histocompatibility complex (MHC) class II regions in rhesus macaques by using a long-read sequencing strategy (Oxford Nanopore Technologies) in concert with adaptive sampling. In particular, the expansion and contraction of the primateDRB-region appears to be a dynamic process that involves the rearrangement of different cassettes of paralogous genes. These chromosomal recombination events are propagated by a conserved pseudogene,DRB6, which features the integration of two retroviral elements. In contrast, theDRAlocus appears to be protected from rearrangements, which may be due to the presence of an adjacently located truncated gene segment,DRB9. With our sequencing strategy, the annotation, evolutionary conservation, and potential function of pseudogenes can be reassessed, an aspect that was neglected by most genome studies in primates. Furthermore, our approach facilitates the characterization and refinement of an animal model essential to study human biology and disease.