bluuebunny/crossref_metadata_2025_split huggingface dataset:
Search for a genetic cause of variably protease-sensitive prionopathy
Authors: Lian Yuan , Kotobelli Keisi , Hall Stacey , Talkowski Michael E , O’Donnell-Luria Anne , Vallabh Sonia M , Appleby Brian S , Minikel Eric Vallabh 
Published: December 2024

AbstractVariably protease-sensitive prionopathy (VPSPr) is a rare, atypical subtype of prion disease in which many patients exhibit a family history of dementia. Rare protein-coding variants inPRNP, which are causal for all known forms of genetic prion disease, have been ruled out in all VPSPr cases to date, leading to suspicion that VPSPr could be caused by variants in other genes or by non-coding variation in or nearPRNP. We performed exome sequencing and targeted sequencing ofPRNPnon-coding regions on genomic DNA from autopsy-confirmed VPSPr patients (N=67) in order to search for a possible genetic cause. Our search identified no potentially causal variants for VPSPr. The common polymorphismPRNPM129V was the largest genetic risk factor for VPSPr, with an odds ratio of 7.0. Other variants in and nearPRNPexhibited association to VPSPr risk only in proportion to their linkage disequilibrium with M129V, and upstream expression quantitative trait loci showed no evidence of independent association to VPSPr risk. We cannot rule out the possibility of causal variants hiding in regions or classes of genetic variation that our search did not canvas. Nevertheless, our data support the classification of VPSPr as a sporadic prion disease.Author SummaryPrion disease is caused by misfolding of the prion protein (PrP), and can be either sporadic genetic, or acquired. Acquired cases arising from infection through dietary or medical routes are exceedingly rare today (<1% of cases). Sporadic cases occur apparently at random, without any major genetic risk factors, and are not passed down to subsequent generations. All cases of genetic prion disease to date have been traced to DNA changes that alter the amino acid sequence of PrP, and children of people with genetic prion disease are at 50/50 risk of inheriting these autosomal dominant DNA changes. Variably protease sensitive prionopathy, or VPSPr, is a rare and unusual subtype of prion disease, in which there are no changes in PrP’s amino acid sequence, and yet, a high proportion of patients appear to have a family history of dementia, although none to date have had family members diagnosed with prion disease specifically. VPSPr is currently categorized as a sporadic prion disease, but it has been speculated that it may have a genetic cause in a different gene or in a region of the PrP gene that does not change the amino acid sequence. Here we performed DNA sequencing on 67 VPSPr cases to search for a genetic cause. We found no DNA changes that could potentially cause VPSPr. While it is difficult to prove the negative — a causal genetic change could still exist in some part of the genome where we did not search — our data support the notion that VPSPr is truly sporadic in nature, and that risk of VPSPr is not transmitted in families.
Integrating patient experiences of healthcare: a critical realist thematic analysis of peri-operative experiences
Authors: Meigh Neil , O’Callaghan Liam , Goldsworthy Adrian , Allan Courtney , Stokes Alison , Mickan Sharon 
Published: December 2024

AbstractBackgroundThe perioperative experience is central to how patients perceive and navigate their care. While existing research has explored broad themes, the nuanced interplay of emotional, psychological, and clinical dimensions remains underexamined. Building on a recent scoping review, this qualitative study sought to explore perioperative patient experiences in greater depth, investigating both pre-established themes and emergent insights.MethodsPatients were invited to share their perioperative journeys through semi-structured interviews, offering detailed accounts of their lived experiences. Using a Critical Realist approach, the study examined both observable factors and underlying mechanisms shaping these experiences. By integrating pre-established themes with participants’ narratives, the study constructed a comprehensive framework reflecting the complexity of patient-reported experiences.AnalysisFour central themes were identified: (1) psychological resilience as a central pillar for patient experience, (2) empowerment and information flow as drivers of patient experience, (3) personalised care as the foundation for patient-centred experience, and (4) integrated care and pain management as central to patient experience. Additionally, social influences and financial barriers emerged as factors shaping the broader context of these experiences, though they were less interconnected with the core themes.DiscussionThis study underscores the multifaceted nature of perioperative patient experiences, where emotional resilience, empowerment, and personalised care are deeply intertwined. These findings highlight the need for health systems and healthcare professionals to address emotional and contextual factors alongside clinical dimensions to improve the overall patient experience.ConclusionBy prioritising the exploration of patient-reported perioperative experiences, this study provides critical insights into the emotional, psychological, and clinical elements that shape care. The integration of these dimensions offers practical guidance for developing patient-centred approaches that align with individuals’ needs and expectations.
SUMO E1 covalent allosteric inhibitors modulate polyamine synthesis via the MAT2A-AdoMetDC axis
Authors: Zhang Shuai , Wang Zhiying , Jiao Yutong , Shi Xiaoyu , Ai Yuanbao , Wang Juanping , Liu Sen 
Published: December 2024

AbstractUpregulation of protein SUMOylation is associated with various diseases, and SUMOylation inhibitors are promising drug candidates. We performed the first virtual screening of SUMO E1 covalent allosteric inhibitors (CAIs) and identified two SUMO E1 CAIs with new scaffolds and covalent warheads. We further demonstrated that these new CAIs perturbed the SUMOylation pathway and protein SUMOylation. Specifically, these CAIs affected the SUMOylation of the methionine adenosyltransferases MAT2A. The inhibition of MAT2A SUMOylation unexpectedly stimulated polyamine synthesis. Lastly, we showed that the combination of SUMO E1 CAIs with a polyamine synthesis inhibitor had synergistic effects in inhibiting T47D cells. Our work demonstrated the first cost-effective virtual screening of SUMO E1 CAIs, found that the downregulation of MAT2A SUMOylation increases polyamine synthesis, and SUMO E1 CAIs can synergize with polyamine synthesis inhibitors. This work would be of great value to the study of SUMOylation, covalent/allosteric drugs, and the polyamine metabolism network.
Inferring gene-pathway associations from consolidated transcriptome datasets: an interactive gene network explorer forTetrahymena thermophila
Authors: Bertagna Michael A. , Bright Lydia J. , Ye Fei , Jiang Yu-Yang , Sarkar Debolina , Pradhan Ajay , Kumar Santosh , Gao Shan , Turkewitz Aaron P. , Tsypin Lev M. Z. 
Published: December 2024

AbstractAlthough an established model organism, Tetrahymena thermophilaremains comparatively inaccessible to high throughput screens, and alternative bioinformatic approaches still rely on unconnected datasets and outdated algorithms. Here, we report a new approach to consolidating RNA-seq and microarray data based on a systematic exploration of parameters and computational controls, enabling us to infer functional gene associations from their co-expression patterns. To illustrate the power of this approach, we took advantage of new data regarding a previously studied pathway, the biogenesis of a secretory organelle called the mucocyst. Our untargeted clustering approach recovered over 80% of the genes that were previously verified to play a role in mucocyst biogenesis. Furthermore, we tested four new genes that we predicted to be mucocyst-associated based on their co-expression and found that knocking out each of them results in mucocyst secretion defects. We also found that our approach succeeds in clustering genes associated with several other cellular pathways that we evaluated based on prior literature. We present theTetrahymenaGene Network Explorer (TGNE) as an interactive tool for genetic hypothesis generation and functional annotation in this organism and as a framework for building similar tools for other systems.Key Pointsur approach integrates nearly 20-year-old microarray and contemporary RNA-seq datasets.rigorously compare co-expression clustering parametrization by way of computational controls.Co-expression clustering identifies known and novel functionally associated genes inTetrahymena.Graphical Abstract
Morphological and Molecular Phylogenetic Characterization of Three New Marine Goniomonad Species
Authors: Phanprasert Yasinee , Kim Sun Young , Kang Nam Seon , Jeong Minseok , Kim Jong Im , Shin Woongghi , Lee Won Je , Kim Eunsoo 
Published: December 2024

ABSTRACTGoniomonads are commonly found heterotrophic biflagellates in both marine and freshwater environments. Despite the high genetic diversity inferred from 18S rDNA data, many goniomonad species remain undescribed. In this study, we established a total of 21 marine goniomonad culture strains, and from these, describe three new species by using light microscopy, electron microscopy, and 18S rDNA phylogeny. Molecular sequence analyses suggest the presence of several distinct sub-lineages within the marine goniomonad clade. Two of these areGoniomonas ulleungensissp. nov. andG. linguasp. nov., which are similar in size, flagellar length, appendage & orientation and by having a tongue-like protrusion at the anterior. The two species can be differentiated by the periplast plate pattern withG. ulleungensisdisplaying one additional plate on the right side.G. duplexsp. nov. differed from these two species by having two unequal flagella with the longer one trailing posteriorly and having the opposite cell orientation when skidding. Comparative analyses of five marine goniomonad species showed that genetically distinct goniomonad groups can be delineated by morphological data as well, and of several morphological features that are of taxonomic utility, the periplast plate pattern, observable by SEM, is particularly informative in goniomonad taxonomy.
Sexual dimorphism in molecular profiles of resting human skeletal muscle and the response to acute exercise and endurance training
Authors: Dreher Simon , Goj Thomas , von Toerne Christine , Hoene Miriam , Irmler Martin , Ouni Meriem , Jähnert Markus , Beckers Johannes , Hrabe de Angelis Martin , Peter Andreas , Moller Anja , Birkenfeld Andreas L. , Schürmann Annette , Hauck Stefanie M. , Weigert Cora 
Published: December 2024

AbstractBiological sex has a strong impact on skeletal muscle metabolism and performance. By a comprehensive investigation of epigenetic, transcriptomic and proteomic differences between female and male skeletal muscle of untrained subjects we provide a molecular basis for the sexual dimorphism of glucose and lipid metabolism. The sex-specific multi-OMICs profiles indicate higher degree of glucose turnover and higher abundance of fast-twitch fibers in males and high degree of lipid handling in females. Eight-week endurance training equalized initial differences toward an endurance-trained proteomic profile in both sexes. The untrained muscle of females was more resistant to an acute exercise challenge since stress-responsive transcripts were predominantly upregulated in males.In myotubes from the same donors, transcriptomic differences were hardly conserved, but could be partially restored by treatment with sex hormones. In conclusion, after only 8 weeks training mitigates deeply rooted sex-specific molecular profiles in skeletal muscle toward a common metabolically beneficial response.
SARS-CoV-2 Nsp14 binds Tollip and activates pro-inflammatory pathways while downregulating interferon-α and interferon-γ receptors
Authors: Thakur Naveen , Chakraborty Poushali , Tufariello JoAnn M. , Basler Christopher F. 
Published: December 2024

AbstractSARS coronavirus 2 (SARS-CoV-2) non-structural protein 14 (Nsp14) possesses an N-terminal exonuclease (ExoN) domain that provides a proofreading function for the viral RNA-dependent RNA polymerase and a C-terminal N7-methyltransferase (N7-MTase) domain that methylates viral mRNA caps. Nsp14 also modulates host functions. This includes the activation of NF-κB and downregulation of interferon alpha/beta receptor 1 (IFNAR1). Here we demonstrate that Nsp14 exerts broader effects, activating not only NF-κB responses but also ERK, p38 and JNK MAP kinase (MAPK) signaling, promoting cytokine production. Further, Nsp14 downregulates not only IFNAR1 but also IFN-γ receptor 1 (IFNGR1), impairing cellular responses to both IFNα and IFNγ. IFNAR1 and IFNGR1 downregulation is via a lysosomal pathway and also occurs in SARS-CoV-2 infected cells. Analysis of a panel of Nsp14 mutants reveals a consistent pattern. Mutants that disable ExoN function remain active, whereas N7-MTase mutations impair both pro-inflammatory pathway activation and IFN receptor downregulation. Innate immune modulating functions also require the presence of both the ExoN and N7-MTase domains likely reflecting the need for the ExoN domain for N7-MTase activity. We further identify multi-functional host protein Tollip as an Nsp14 interactor. Interaction requires the phosphoinositide-binding C2 domain of Tollip and sequences C-terminal to the C2 domain. Full length Tollip or regions encompassing the Nsp14 interaction domain are sufficient to counteract both Nsp14-mediated and Nsp14-independent activation of NF-κB. Knockdown of Tollip partially reverses IFNAR1 and IFNGR1 downregulation in SARS-CoV-2 infected cells, suggesting relevance of Nsp14-Tollip interaction for Nsp14 innate immune evasion functions.SignificanceSARS-CoV-2 protein Nsp14 both activates NF-κB, which promotes virus replication and inflammation, and downregulates IFNAR1, which can render infected cells resistant to the antiviral effects of IFN-α/β. Our study demonstrates that Nsp14 also activates MAPK signaling and downregulates IFNGR1, causing broader impacts than previously recognized. Data from a panel of Nsp14 mutants suggests a common underlying effect of Nsp14 may be responsible for its multiple innate immune activities. We further describe a novel interaction between Nsp14 and Tollip, a selective autophagy receptor. We show that Tollip expression downregulates Nsp14 activation of NF-κB and that Tollip knockdown reverses IFNAR1 and IFNGR1 downregulation in SARS-CoV-2 infection, suggesting that Tollip functions as a regulator of Nsp14 innate immune modulation.
Zinc is a Key Regulator of the Sperm-Specific K+Channel (Slo3) Function
Authors: Andriani Rizki Tsari , Pipatpolkai Tanadet , Miyata Haruhiko , Ikawa Masahito , Okamura Yasushi , Kawai Takafumi 
Published: December 2024

AbstractThe voltage- and pH-gated Slo3 potassium channel is exclusively expressed in mammalian spermatozoa. Its sensitivity to both voltage and alkalization plays a crucial role in sperm fertility, which is tightly coupled to the capacitation process. Here we show that sperm-enriched divalent cation Zn2+undergoes dynamic alteration in spermatozoa during capacitation. We also found that intracellular Zn2+regulates alkalinization-induced hyperpolarization in mice spermatozoa which is mediated by Slo3 channel. Further examination of zinc regulation in mouse Slo3 (mSlo3) revealed that, inXenopusoocyte expression system, intracellular zinc directly inhibits mouse Slo3 currents in dose-dependent manner at micromolar concentrations, with exceptionally slow dissociation. By combining MD simulations and electrophysiology, we also identified amino acid residues contributing to the Zn2+slow dissociation from Slo3 channels. Our studies uncover the importance of intracellular zinc dynamics and its regulatory role in ion channels during sperm capacitation.
Angiotensin peptides enhance SARS-CoV-2 spike protein binding to its host cell receptors
Authors: Oliveira Katelin X. , Suzuki Yuichiro J. 
Published: December 2024

AbstractSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus that caused the Coronavirus Disease 2019 (COVID-19) pandemic, has a spike glycoprotein that is involved in recognizing and fusing to host cell receptors, such as angiotensin-converting enzyme 2 (ACE2), neuropilin-1 (NRP1), and AXL tyrosine-protein kinase. Since the major spike protein receptor is ACE2, an enzyme that regulates angiotensin II (1-8), this study tested the hypothesis that angiotensin II (1-8) influences the binding of the spike protein to its receptors. While angiotensin II (1-8) did not influence spike-ACE2 binding, we found that it significantly enhances spike-AXL binding. Our experiments showed that longer lengths of angiotensin, such as angiotensin I (1-10), did not significantly affect spike-AXL binding. In contrast, shorter lengths of angiotensin peptides, in particular, angiotensin IV (3-8), strongly increased spike-AXL binding. Angiotensin IV (3-8) also enhanced spike protein binding to ACE2 and NRP1. The discovery of the enhancing effects of angiotensin peptides on spike-host cell receptor binding may suggest that these peptides could be pharmacological targets to treat COVID-19 and post-acute sequelae of SARS-CoV-2 (PASC), which is also known as long COVID.
Hydrophysiology NMR reveals mechanisms of steady-state water exchange in neural tissue
Authors: Williamson Nathan H. , Ravin Rea , Cai Teddy X. , Rey Julian A. , Basser Peter J. 
Published: December 2024

SUMMARYWater molecules exchange incessantly across cell membranes and among different environments within the cell, but it is not known what the dominant transport pathways are and whether they are active or passive. We have developed realtime NMR hydrophysiology methods to study steady-state water exchange and diffusion in viableex vivoneonatal mouse spinal cord samples. We find that water exchange is not active but is linked to tonicity maintained by active transport. Exchange slows following sodium–potassium pump inhibition but recovers to a normal rate after adding extracellular osmolytes. Additional information from apparent water diffusion coefficients (ADC) differentiates normal and inactive samples regardless of tonicity. Data and modeling suggest a multisite exchange mechanism in which tonicity modulates the dominant apparent exchange pathway between fast transmembrane exchange and slow intracellular exchange. The transmembrane pathway has a high activation energy but does not require ions, suggesting that in this pathway exchange likely occurs through the lipid bilayer rather than through channels or cotransporters. These methods may one day be translated to clinical MRI scanners to determine features of the cellular statein vivo. steady state water exchange, homeostasis, diffusion exchange spectroscopy, DEXSY, tissue microstructure, porous media, membrane permeability, low-field single-sided NMR, apparent diffusion coefficient, ADC, gray matter
Development of an enhanced anti-pan-N-formylmethionine-specific antibody
Authors: Kim Dasom , Park Kyu-Sang , Hwang Cheol-Sang 
Published: December 2024

ABSTRACTBoth bacterial and eukaryotic ribosomes can initiate protein synthesis with formylmethionine (fMet), but detecting fMet-bearing peptides and fMet-bearing proteins has been challenging due to the lack of effective anti-pan-fMet antibodies. Previously, we developed a polyclonal anti-fMet antibody using a fMet-Gly-Ser-Gly-Cys pentapeptide that detects those fMet-bearing peptides and fMet-bearing proteins regardless of their sequence context. In this study, we significantly improved the antibody’s specificity and affinity by using a mixture of fMet-Xaa-Cys (fMXC) tripeptides (Xaa, any of the 20 amino acids) as the immunogen. This newly optimized anti-fMet antibody is a powerful, cost-effective tool for detecting fMet-bearing proteins across species. Furthermore, this approach provides a foundation for developing anti-pan-specific antibodies targeting other N-terminal modifications through acylation, alkylation, oxidation, or arginylation, etc.METHOD SUMMARYfMet-Gly-Ser-Gly-Cys (fMGSGC), fMet-dPEG4-Cys (fMdPEG4C), and fMet-Xaa-Cys (fMXC; Xaa, any of the 20 amino acids) were used as antigens to generate anti-pan-fMet-specific antibodies (anti-fMet antibodies). The quality of the raised antibodies was evaluated by immunoblotting using lysates fromEscherichia coli(E. coli) DH5α cells and human kidney HK2 cells, as well as by enzyme-linked immunosorbent assay (ELISA) with purified fMet-bearing (fMet-) proteins and their unformylated counterparts.
Cell surface crowding is a tunable biophysical barrier to cell-cell fusion
Authors: Lee Daniel S.W. , Oster Liya F. , Son Sungmin , Fletcher Daniel A. 
Published: December 2024

SummaryCell-cell fusion is fundamental to developmental processes such as muscle formation, as well as to viral infections that cause pathological syncytia. An essential step in fusion is close membrane apposition, but cell membranes are crowded with proteins, glycoproteins, and glycolipids, all of which must be cleared before a fusion pore can be nucleated. Here, we find that cell surface crowding drastically reduces fusogenicity in multiple systems, independent of the method for driving fusion. We estimate that cell surface crowding presents an energetic barrier to membrane apposition on the scale of ∼100kBT, greater than that of bare membrane fusion. We show that increasing cell surface crowding reduces fusion efficiency of PEG-mediated and fusogen-mediated cell-cell fusion, as well as synthetic membranes under force. Interestingly, we find that differentiating myoblasts naturally decrease cell surface crowding prior to fusion. Cell surface crowding presents an underappreciated biophysical barrier that may be tuned developmentally and could be targeted externally to control tissue-specific cell-cell fusion.
The DiaGame Study: Multimodal Data Collection in Free-Living Conditions Using Consumer-Level Wearable Devices and Apps in People with Diabetes
Authors: de Vries Ryan , Reinders Edouard F.H. , de Carvalho Danilo Ferreira , Cruts – Van de Meulengraaf Elma M.W.L. , van Gorp Pieter M.E. , Wouters - van Poppel Pleun C.M. , Kaymak Uzay , Hilbers Peter A.J. , van Riel Natal A.W. , Haak Harm R. 
Published: December 2024

AbstractThe everlasting interest in precision medicine has instigated a need for patient-specific multidimensional data collection. By leveraging consumer-level wearable devices and applications we can support this need by collecting multimodal data in uncontrolled free-living conditions. We used a continuous glucose monitor, a smartwatch with in-house developed application, and a smartphone application over a period of 14 days to collect data from 60 participants with diabetes. Data were collected on 77,683 CGM measurements, 4,073 moods, 3,517 meals, 1,394 insulin injections, and 1,364 bouts of physical activity. Participants were able to effectively use the devices and applications, with 45 participants reporting data on all modalities and all participants reporting data on at least two modalities (in addition to the data collected from the smartwatch’s internal sensors). These findings highlight the efficiency and effectiveness of consumer-level wearable devices to collect data from the comfort of the people’s homes. Thereby, facilitating the need for a cost-effective and scalable approach for precision monitoring to the public.