bluuebunny/crossref_metadata_2025_split huggingface dataset:
The distinctive mechanical and structural signatures of residual force enhancement in myofibers
Authors: Hessel Anthony L. , Kuehn Michel , Palmer Bradley M. , Nissen Devin , Mishra Dhruv , Joumaa Venus , Freundt Johanna , Ma Weikang , Nishikawa Kiisa C. , Irving Thomas , Linke Wolfgang A. 
Published: February 2023

AbstractIn muscle, titin proteins connect myofilaments together and are thought to be critical for contraction, especially during residual force enhancement (RFE) when force is elevated after an active stretch. We investigated titin’s function during contraction using small-angle X-ray diffraction to track structural changes before and after 50% titin cleavage and in the RFE-deficient,mdmtitin mutant. We report that the RFE state is structurally distinct from pure isometric contractions, with increased thick filament strain and decreased lattice spacing, most likely caused by elevated titin-based forces. Furthermore, no RFE structural state was detected inmdmmuscle. We posit that decreased lattice spacing, increased thick filament stiffness, and increased non-crossbridge forces are the major contributors to RFE. We conclude that titin directly contributes to RFE.One-Sentence SummaryTitin contributes to active force production and residual force enhancement in skeletal muscles.
FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity
Authors: Wieder Nicolas , Fried Juliana Coraor , Kim Choah , Sidhom Eriene-Heidi , Brown Matthew R. , Marshall Jamie L. , Arevalo Carlos , Dvela-Levitt Moran , Kost-Alimova Maria , Sieber Jonas , Gabriel Katlyn R. , Pacheco Julian , Clish Clary , Abbasi Hamdah Shafqat , Singh Shantanu , Rutter Justine , Therrien Martine , Yoon Haejin , Lai Zon Weng , Baublis Aaron , Subramanian Renuka , Devkota Ranjan , Small Jonnell , Sreekanth Vedagopuram , Han Myeonghoon , Lim Donghyun , Carpenter Anne E. , Flannick Jason , Finucane Hilary , Haigis Marcia C. , Claussnitzer Melina , Sheu Eric , Stevens Beth , Wagner Bridget K. , Choudhary Amit , Shaw Jillian L. , Pablo Juan Lorenzo , Greka Anna 
Published: February 2023

SummaryCellular exposure to free fatty acids (FFA) is implicated in the pathogenesis of obesity-associated diseases. However, studies to date have assumed that a few select FFAs are representative of broad structural categories, and there are no scalable approaches to comprehensively assess the biological processes induced by exposure to diverse FFAs circulating in human plasma. Furthermore, assessing how these FFA- mediated processes interact with genetic risk for disease remains elusive. Here we report the design and implementation of FALCON (Fatty Acid Library for Comprehensive ONtologies) as an unbiased, scalable and multimodal interrogation of 61 structurally diverse FFAs. We identified a subset of lipotoxic monounsaturated fatty acids (MUFAs) with a distinct lipidomic profile associated with decreased membrane fluidity. Furthermore, we developed a new approach to prioritize genes that reflect the combined effects of exposure to harmful FFAs and genetic risk for type 2 diabetes (T2D). Importantly, we found that c-MAF inducing protein (CMIP) protects cells from exposure to FFAs by modulating Akt signaling and we validated the role of CMIP in human pancreatic beta cells. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism.HighlightsFALCON (Fatty Acid Library for Comprehensive ONtologies) enables multimodal profiling of 61 free fatty acids (FFAs) to reveal 5 FFA clusters with distinct biological effectsFALCON is applicable to many and diverse cell typesA subset of monounsaturated FAs (MUFAs) equally or more toxic than canonical lipotoxic saturated FAs (SFAs) leads to decreased membrane fluidityNew approach prioritizes genes that represent the combined effects of environmental (FFA) exposure and genetic risk for diseaseC-Maf inducing protein (CMIP) is identified as a suppressor of FFA-induced lipotoxicity via Akt-mediated signaling
Quantitative model of aging-related muscle degeneration: a Drosophila study
Authors: Chechenova Maria , Stratton Hannah , Kiani Kaveh , Gerberich Erik , Alekseyenko Alesia , Tamba Natasya , An SooBin , Castillo Lizzet , Czajkowski Emily , Talley Christina , Bryantsev Anton 
Published: February 2023

ABSTRACTChanges in the composition and functionality of somatic muscles is a universal hallmark of aging that is displayed by a wide range of species. In humans, complications arising from muscle decline due to sarcopenia aggravate morbidity and mortality rates. The genetics of aging-related deterioration of muscle tissue is not well understood, which prompted us to characterize aging-related muscle degeneration inDrosophila melanogaster(fruit fly), a leading model organism in experimental genetics. Adult flies demonstrate spontaneous degeneration of muscle fibers in all types of somatic muscles, which correlates with functional, chronological, and populational aging. Morphological data imply that individual muscle fibers die by necrosis. Using quantitative analysis, we demonstrate that muscle degeneration in aging flies has a genetic component. Chronic neuronal overstimulation of muscles promotes fiber degeneration rates, suggesting a role for the nervous system in muscle aging. From the other hand, muscles decoupled from neuronal stimulation retain a basal level of spontaneous degeneration, suggesting the presence of intrinsic factors. Based on our characterization,Drosophilacan be adopted for systematic screening and validation of genetic factors linked to aging-related muscle loss.
Butyrate, valerate, and niacin ameliorate anaphylaxis by suppressing IgE-dependent mast cell activation: Roles of GPR109A, PGE2, and epigenetic regulation
Authors: Nagata Kazuki , Ando Daisuke , Ashikari Tsubasa , Ito Kandai , Miura Ryosuke , Fujigaki Izumi , Ando Miki , Ito Naoto , Kawazoe Hibiki , Iizuka Yuki , Inoue Mariko , Yashiro Takuya , Hachisu Masakazu , Kasakura Kazumi , Nishiyama Chiharu 
Published: February 2023

AbstractShort chain fatty acids (SCFAs) were recently shown to modulate the development and functions of immune-related cells. However, the molecular mechanisms by which SCFAs regulate mast cells (MCs) are not fully understood. We found that the oral administration of valerate or butyrate ameliorated passive systemic anaphylaxis in mice. Butyrate and valerate suppressed the IgE-mediated degranulation of bone marrow-derived MCs, which were eliminated by pertussis toxin and by the knockdown ofGpr109a. A treatment with trichostatin A suppressed IgE-mediated MC activation and reduced the surface expression level of FcεRI on MCs. Acetylsalicylic acid and indomethacin attenuated the suppressive effects of SCFAs on degranulation. The degranulation degree was significantly decreased by the treatment with PGE2whose release from MCs was markedly enhanced by SCFAs. The SCFA-mediated amelioration of anaphylaxis was exacerbated by COX inhibitors and an EP3 antagonist. The administration of niacin, a ligand of GPR109A, alleviated the symptoms of passive cutaneous anaphylaxis, which was inhibited by COX inhibitors and the EP3 antagonist.Key MessagesShort chain fatty acids (SCFAs), particularly butyrate and valerate, suppress the IgE-mediated activation of mast cells (MCs)in vivoandin vitro.SCFAs enhance the release of PGE2from MCs, which inhibits the IgE-mediated activation of MCs.Niacin, a ligand of GPR109A, ameliorates IgE-dependent anaphylaxis.The administration of COX inhibitors or an antagonist of PGE2receptor 3 (EP3) inhibited the suppressive effects of butyrate and niacin on IgE-dependent anaphylaxis.
Feasibility randomised controlled trial of online group Acceptance and Commitment Therapy for Functional Cognitive Disorder (ACT4FCD)
Authors: Poole Norman , Cope Sarah , Vanzan Serena , Duffus Aimee , Mantovani Nadia , Smith Jared , Barrett Barbara , Tokley Melanie , Scicluna Martin , Beardmore Sarah , Turner Kati , Edwards Mark , Howard Rob 
Published: February 2023

AbstractIntroductionFunctional cognitive disorder is seen increasingly in clinics commissioned to assess cognitive disorders. Patients complain of frequent cognitive, especially memory, failures. The diagnosis can be made clinically, and unnecessary investigations avoided. While there is some evidence that psychological treatments can be helpful, they are not routinely available. Therefore, we have developed a brief psychological intervention using the principles of Acceptance and Commitment Therapy (ACT) that can be delivered in groups and online. We are conducting a feasibility study to assess whether the intervention can be delivered within a randomised controlled trial. We aim to study the feasibility of recruitment, willingness to be randomised to intervention or control condition, adherence to the intervention, completion of outcome measures, and acceptability of treatment.Methods and analysisWe aim to recruit 48 participants randomised 50:50 to either the ACT intervention and Treatment as Usual (TAU), or TAU alone. ACT will be provided to participants in the treatment arm following completion of baseline outcome measures. Completion of these outcome measures will be repeated at 8, 16, and 26 weeks. The measures will assess several domains including psychological flexibility, subjective cognitive symptoms, mood and anxiety, health related quality of life and functioning, healthcare utilisation, and satisfaction with care and participant-rated improvement. Fifteen participants will be selected for in-depth qualitative interviews about their experiences of living with FCD and of the ACT intervention.Ethics and disseminationThe study received a favourable opinion from the South East Scotland Research Ethics Committee 02 on 30th September 2022 (REC reference: 22/SS/0059). HRA approval was received on 1stNovember 2022 (IRAS 313730). The study has been registered with the ISRCTN (ISRCTN12939037). The results will be published in full in an open access journal.ISRCTN Registrationhttps://doi.org/10.1186/ISRCTN12939037Grant NumberNational Institute for Health and Care Research (NIHR) grant number: NIHR202743Strengths and limitations of this studyNovel intervention with potential to be delivered at scaleAdherence to principles of an evidence-based intervention (ACT)Utilising qualitative and quantitative methodologies which is key to contextualising patient experiences in a clinically meaningful measurement frameworkRecruiting from the full range of services that assess cognition in adults in the UKParticipants not blinded to their intervention
OptIC Notch reveals mechanism that regulates receptor interactions with CSL
Authors: Townson Jonathan M. , Gomez-Lamarca Maria J. , Santa Cruz Mateos Carmen , Bray Sarah J. 
Published: February 2023

AbstractActive Notch signalling is elicited through receptor-ligand interactions that result in release of the Notch intracellular domain (NICD), which translocates into the nucleus. NICD activates transcription at target genes forming a complex with the DNA-binding transcription factor CSL (CBF1/Su(H)/Lag-1) and co-activator Mastermind. Despite this, CSL lacks its own nuclear localisation sequence, and it remains unclear where the tripartite complex is formed. To probe mechanisms involved, we designed an optogenetic approach to control NICD release (OptIC-Notch) and monitored consequences on complex formation and target gene activation. Strikingly we observed that, when uncleaved, OptIC-Notch sequestered CSL in the cytoplasm. Hypothesising that exposure of a juxta membrane ΦWΦP motif is key to sequestration, we masked this motif with a second light sensitive domain in OptIC-Notch{ω}, which was sufficient to prevent CSL sequestration. Furthermore, NICD produced by light-induced cleavage of OptIC-Notch or OptIC-Notch{ω} chaperoned CSL into the nucleus and induced target gene expression, showing efficient light controlled activation. Our results demonstrate that exposure of the ΦWΦP motif leads to CSL recruitment and suggest this can occur in the cytoplasm prior to nuclear entry.Summary statementLight controlled exposure of the Notch ΦWΦP motif leads to CSL sequestration and suggest this interaction could occur prior to nuclear entry during normal signalling.
Cerebellar Morphological Differences in Bipolar Disorder Type I
Authors: Harmata Gail I. S. , Barsotti Ercole John , Casten Lucas G. , Fiedorowicz Jess G. , Williams Aislinn , Shaffer Joseph J. , Richards Jenny Gringer , Sathyaputri Leela , Schmitz Samantha L. , Christensen Gary E. , Long Jeffrey D. , Gaine Marie E. , Xu Jia , Michaelson Jake J. , Wemmie John A. , Magnotta Vincent A. 
Published: February 2023

AbstractBackgroundThe neural underpinnings of bipolar disorder (BD) remain poorly understood. The cerebellum is ideally positioned to modulate emotional regulation circuitry yet has been understudied in BD. Previous studies have suggested differences in cerebellar activity and metabolism in BD, however findings on cerebellar structural differences remain contradictory.MethodsWe collected 3T anatomical MRI scans from participants with (N = 131) and without (N = 81) BD type I. Differences in cerebellar volumes were assessed along with factors that influence the results.ResultsThe cerebellar cortex was smaller bilaterally in participants with BD. Polygenic propensity score (bipolar N = 103, control N = 64) did not predict any cerebellar volumes, suggesting that non-genetic factors may have greater influence on the cerebellar volume difference we observed in BD. Cerebellar white matter volumes increased with more adverse childhood events, but we did not observe any associations with parental psychiatric illness. We also evaluated time from onset and symptom burden and found no associations with cerebellar volumes, suggesting neurodevelopment may differ prior to onset. Finally, we found taking sedatives was associated with larger cerebellar white matter and non-significantly larger cortical volume.LimitationsThis study was cross-sectional, limiting interpretation of possible mechanisms. Most of our participants were White, which could limit the generalizability. Additionally, we did not account for potential polypharmacy interactions.ConclusionsThese findings suggest that external influences, such as medications, may influence cerebellum structure in BD and may mask underlying differences. Accounting for medication may be critical for consistent findings in future studies.
Field cancerization impacts tumor development, T-cell exhaustion and clinical outcomes in bladder cancer
Authors: Strandgaard Trine , Nordentoft Iver , Birkenkamp-Demtröder Karin , Salminen Liina , Prip Frederik , Rasmussen Julie , Andreasen Tine Ginnerup , Lindskrog Sia Viborg , Christensen Emil , Lamy Philippe , Knudsen Michael , Steiniche Torben , Jensen Jørgen Bjerggaard , Dyrskjøt Lars 
Published: February 2023

AbstractBladder field cancerization may be associated with disease outcome in patients with bladder cancer. To investigate this, we analyzed biopsies from bladder urothelium and urine samples by genomics and proteomics analyses. Samples were procured from multiple timepoints from 134 patients with early stage bladder cancer and detailed long term follow-up. We measured the field cancerization in normal-appearing bladder biopsies and found that high levels were associated with high tumor mutational burden, high neoantigen load, and high tumor-associated CD8 T-cell exhaustion. Non-synonymous mutations in known bladder cancer driver genes such asKDM6AandTP53were identified as early disease drivers in normal urothelium. High field cancerization was associated with worse outcome but not with response to BCG. The level of urinary tumor DNA (utDNA) reflected the bladder tumor burden and originated from both tumors and field cancerization. High utDNA levels after BCG were associated with worse clinical outcomes for the patients. Our results indicate that the level of field cancerization may affect clinical outcome, tumor development and immune responses. utDNA measurements have significant prognostic value and reflect the disease status of the bladder.
Rie1 and Sgn1 form an RNA-binding complex that enforces the meiotic entry cell fate decision
Authors: Gaspary Alec , Laureau Raphaelle , Dyatel Annie , Dursuk Gizem , Berchowitz Luke E. 
Published: February 2023

AbstractBudding yeast cells have the capacity to adopt few but distinct physiological states depending on environmental conditions. Vegetative cells proliferate rapidly by budding while spores can survive prolonged periods of nutrient deprivation and/or desiccation. Whether or not a yeast cell will enter meiosis and sporulate represents a critical decision which could be lethal if made in error. Most cell fate decisions, including those of yeast, are understood as being triggered by the activation of master transcription factors. However, mechanisms that enforce cell fates post-transcriptionally have been more difficult to attain. Here, we perform a forward genetic screen to determine RNA-binding proteins that affect meiotic entry at the post-transcriptional level. Our screen revealed several candidates with meiotic entry phenotypes, the most significant beingRIE1which encodes an RRM-containing protein. We demonstrate that Rie1 binds RNA, is associated with the translational machinery, and acts post-transcriptionally to enhance protein levels of the master transcription factor Ime1 in sporulation conditions. We also identified a physical binding partner of Rie1, Sgn1, which is another RRM-containing protein that plays a role in timely Ime1 expression. We demonstrate that these proteins act independently of cell size regulation pathways to promote meiotic entry. We propose a model explaining how constitutively expressed RNA-binding proteins, such as Rie1 and Sgn1, can act in cell-fate decisions both as switch-like enforcers and as repressors of spurious cell fate activation.
Ribosomal intergenic spacers are filled with transposon remnants
Authors: Bendich Arnold J. , Rogers Scott O. 
Published: February 2023

AbstractEukaryotic ribosomal DNA (rDNA) comprises tandem units of highly-conserved coding genes separated by rapidly-evolving spacer DNA. The spacers of all 12 species examined were filled with short direct repeats (DRs) and multiple long tandem repeats (TRs), completing the rDNA maps that previously contained unannotated and inadequately studied sequences. The external transcribed spacers also were filled with DRs and some contained TRs. We infer that the spacers arose from transposon insertion, followed by their imprecise excision, leaving short DRs characteristic of transposon visitation. The spacers provided a favored location for transposon insertion because they occupy loci containing hundreds to thousands of gene repeats. The spacers’ primary cellular function may be to link one rRNA transcription unit to the next, whereas transposons flourish here because they have colonized the most frequently-used part of the genome.Author SummaryThe DNA loci containing the ribosomal RNA genes (the rDNA) in eukaryotes are puzzling. The sections encoding the rRNA are so highly conserved that they can be used to assess evolutionary relationships among diverse eukaryotes, yet the rDNA sequences between the rRNA genes (the intergenic spacer sequences; IGS) are among the most rapidly evolving in the genome, including varying within and between species and between individuals of a species, and within cells of an individual. Here we report the presence of large numbers of direct repeats (DRs) throughout the IGSs of a diverse set of organisms. Parasitic DNA and RNA elements often leave short DRs when they are excised resulting in “molecular scars” in the DNA. These “scars” are absent from the coding sections of the rDNA repeats, indicating that the IGSs have long been targets for integration of these parasitic elements that have been eliminated from the coding sections by selection. While these integration events are mostly detrimental to the organism, occasionally they have caused beneficial changes in eukaryotes, thus allowing both the parasites and the hosts to survive and co-evolve.
Temporal dynamics of trauma memory persistence
Authors: Bonsall Michael B. , Holmes Emily A. 
Published: February 2023

AbstractTraumatic events lead to distressing memories, but such memories are made all the worse when they intrude to mind unbidden and recurrently. Intrusive memories are a hallmark of several mental health disorders including posttraumatic stress disorder (PTSD) and can persist for years. Critically, the reduction of intrusive memories provides a treatment target. While cognitive models for psychological trauma exist, these lack formal quantitative structure and robust empirical validation. Here we develop a mechanistically-driven, quantitative framework to extend understanding of the temporal dynamic processes of trauma memory. We show how the marginal gains of interventions for intrusive memories can be enhanced as key properties of the intervention vary. Validating the framework against empirical data highlights that while emerging interventions to reduce occurrence of intrusive memories can be effective, counter-intuitively, maintaining these memories in a sufficiently reactivated state is essential for preventing their persistence.Author SummaryIntrusive memories and flashbacks after trauma are prominent in several mental disorders. Quantifying these intrusions is the aim of the current study. While many conceptual models for trauma memory exist, none provide a mechanistic framework for validating experimental or clinical evidence. Our approach is to develop a probabilistic description of memory mechanisms to link to the broader goals of trauma treatment. Analysis shows how critical attributes of the framework such as intervention strength and reminder strength determine success in managing intrusive memories. Validation with empirical data shows how the framework can be parameterized and predictions evaluated against observed outcomes. In this way neural mechanisms associated with memory can be combined with broader cognitive processes.