bluuebunny/crossref_metadata_2025_split huggingface dataset:
SCUBE-1 in The Diagnosis and Follow-Up Of Subclinical Atherosclerosis in The Experimental Diabetes Mellitus and Obesity Model
Authors: KÖK Mehmet , ASLANKOÇ Rahime , ÖZMEN Özlem , DORA Devrim , ELLIDAG Hamit Yasar 
Published: October 2023

ABSCTRACTBACKGROUNDObesity and diabetes mellitus (DM) is a metabolic disease that is a global problem, the most crucial complication of which is atherosclerotic cardiovascular disease resulting from endothelial dysfunction and accompanying platelet hyperactivity. The presence of the SCUBE-1 protein has been observed within vascular endothelial cells and platelets, both recognized for their pivotal involvement in the arterial thrombosis mechanism. The objective of this research is to examine the utility of serum SCUBE-1 levels in diagnosing and monitoring subclinical atherosclerosis in experimentally induced DM and obese rats.METHODSThe study comprised a cohort of 28 male Sprague‒Dawleyrats, which encompassed the following groups: the obese group subjected to a high-fat diet (HFD), the TII-DM group administered HFD in combination with a single dose of streptozocin (STZ), the TI-DM group treated solely with STZ, and the control group. Serum SCUBE1 was analyzed using the enzyme-linked immunosorbent assay method, and caspase-3 (Cas-3), interleukin-6 (IL-6), interferon-gamma (INF-gamma) and superoxide dismutase (SOD) expression in the liver and pancreas of rats were evaluated using immunohistochemical methods.RESULTSSerum SCUBE1 levels were significantly higher in the obese and DM groups than in the control group, but there was no significant difference among the obese, TI-DM and TII-DM groups. The study identified a significant relationship between serum SCUBE1 level and hepatic CAS3, IL-6 and SOD expression and pancreatic SOD expression.CONCULISONSCUBE1 can be used as a promising novel marker for the diagnosis and monitoring of subclinical atherosclerosis in individuals with obesity, TI-DM, and TII-DM
How tool combinations in different pipeline versions affect the outcome in RNA-seq analysis
Authors: Perelo Louisa Wessels , Gabernet Gisela , Straub Daniel , Nahnsen Sven 
Published: October 2023

ABSTRACTData analysis tools are continuously changed and improved over time. In order to test how these changes influence the comparability between analyses, the output of different workflow options of the nf-core/rnaseq pipeline were compared. Five different pipeline settings (STAR+Salmon, STAR+RSEM, STAR+featureCounts, HiSAT+featureCounts, pseudoaligner Salmon) were run on three datasets (human, Arabidopsis, zebrafish) containing spike-ins of the External RNA Control Consortium (ERCC). Fold change ratios and differential expression of genes and spike-ins were used for comparative analyses of the different tools and versions settings of the pipeline. An overlap of 85% for differential gene classification between pipelines could be shown. Genes interpreted with a bias were mostly those present at lower concentration. Also, the number of isoforms and exons per gene were determinants. Previous pipeline versions using featureCounts showed a higher sensitivity to detect one-isoform genes like ERCC. To ensure data comparability in long-term analysis series it would be recommendable to either stay with the pipeline version the series was initialized with or to run both versions during a transition time in order to ensure that the target genes are addressed the same way.
LGI1 autoantibodies enhance synaptic transmission by presynaptic Kv1 loss and increased action potential broadening
Authors: Ritzau-Jost Andreas , Gsell Felix , Sell Josefine , Sachs Stefan , Montanaro Jacqueline , Kirmann Toni , Maaß Sebastian , Irani Sarosh R. , Werner Christian , Geis Christian , Sauer Markus , Shigemoto Ryuichi , Hallermann Stefan 
Published: October 2023

AbstractBackground and ObjectivesAutoantibodies against the neuronally secreted protein leucine-rich glioma inactivated 1 (LGI1) cause the most common subtype of autoimmune limbic encephalitis associated with seizures and memory deficits. LGI1 and its receptor ADAM22 are part of a transsynaptic protein complex that includes several proteins involved in presynaptic neurotransmitter release and postsynaptic glutamate sensing. Autoantibodies against LGI1 increase excitatory synaptic strength, but studies that genetically disrupt the LGI1-ADAM22 complex report a reduction in postsynaptic glutamate receptor-mediated responses. Thus, the mechanisms underlying the increased synaptic strength induced by LGI1 autoantibodies remain elusive, and the contributions of presynaptic molecules to the LGI1-transsynaptic complex remain unclear. We therefore investigated the presynaptic mechanisms that mediate autoantibody-induced synaptic strengthening.MethodsWe studied the effects of patient-derived purified polyclonal LGI1 autoantibodies on synaptic structure and function by combining direct patch-clamp recordings from presynaptic boutons and somata of hippocampal neurons with super-resolution light and electron microscopy of hippocampal cultures and acute brain slices. We also identified the protein domain mediating the presynaptic effect using domain-specific patient-derived monoclonal antibodies.ResultsLGI1 autoantibodies dose-dependently increased short-term depression during high-frequency transmission, consistent with increased release probability. The increased neurotransmission was not related to presynaptic calcium channels, as presynaptic Cav2.1 channel density, calcium current amplitude, and calcium channel gating were unaffected by LGI1 autoantibodies. In contrast, application of LGI1 autoantibodies homogeneously reduced Kv1.1 and Kv1.2 channel density on the surface of presynaptic boutons. Direct presynaptic patch-clamp recordings revealed that LGI1 autoantibodies cause a pronounced broadening of the presynaptic action potential. Domain-specific effects of LGI1 autoantibodies were analysed at the soma, where polyclonal LGI1 autoantibodies and patient-derived monoclonal autoantibodies targeting the Epitempin-domain but not the Leucin rich repeat-domain induced action potential broadening.DiscussionOur results indicate that LGI1 autoantibodies do not affect calcium channel density or function, but reduce the density of both Kv1.1 and Kv1.2 on presynaptic boutons, thereby broadening the presynaptic action potential and increasing neurotransmitter release. This study provides a molecular explanation for the neuronal hyperactivity induced by LGI1 autoantibodies.
Natural malaria infection elicits rare but potent neutralizing antibodies to the blood-stage antigen RH5
Authors: Wang Lawrence T. , Cooper Andrew J.R. , Farrell Brendan , Miura Kazutoyo , Diouf Ababacar , Müller-Sienerth Nicole , Crosnier Cécile , Purser Lauren , Maciuszek Maciej , Barrett Jordan R. , McHugh Kirsty , Tucker Courtney , Li Shanping , Doumbo Safiatou , Doumtabe Didier , Pyo Chul-Woo , Nielsen Carolyn M. , Silk Sarah E. , Kayentao Kassoum , Ongoiba Aissata , Zhao Ming , Nguyen Doan C. , Lee F. Eun-Hyung , Minassian Angela M. , Geraghty Daniel E. , Traore Boubacar , Seder Robert A. , Crompton Peter D. , Wright Gavin J. , Long Carole A. , Draper Simon J. , Higgins Matthew K. , Tan Joshua 
Published: October 2023

ABSTRACTPlasmodium falciparumRH5 is the most advanced blood-stage malaria vaccine candidate and is under evaluation for efficacy in endemic regions, emphasizing the need to study the underlying antibody response to RH5 during natural infection. Here, we found that RH5-reactive B cells were rare in malaria-exposed individuals despite repeated infections over multiple years. RH5-specific monoclonal antibodies isolated from these individuals were extensively mutated but mostly targeted non-neutralizing epitopes, in contrast to antibodies from RH5-vaccinated, malaria-naive individuals. However, infection-derived MAD8-151 and MAD8-502 were among the most potent neutralizers out of 186 antibodies isolated from both cohorts and target the same epitopes as the most effective vaccine-induced antibodies. Binding to basigin receptor-proximal epitopes was the primary factor governing the potency of RH5-specific antibodies from both natural infection and vaccination, followed by the strength of binding. These results indicate a clear strategy for the development of next-generation RH5 vaccines for use in malaria-endemic regions.
Recurrent duplication and diversification of a vital DNA repair gene family across Drosophila
Authors: Brand Cara L. , Oliver Genevieve T. , Farkas Isabella Z. , Levine Mia T. 
Published: October 2023

ABSTRACTMaintaining genome integrity is vital for organismal survival and reproduction. Essential, broadly conserved DNA repair pathways actively preserve genome integrity. However, many DNA repair proteins evolve adaptively. Ecological forces like UV exposure are classically cited as drivers of DNA repair evolution. Intrinsic forces like repetitive DNA, which can also imperil genome integrity, have received less attention. We recently reported that aDrosophila melanogaster-specific DNA satellite array triggered species-specific, adaptive evolution of a DNA repair protein called Spartan/MH. The Spartan family of proteases cleave hazardous, covalent crosslinks that form between DNA and proteins (“DNA-protein crosslink repair”). Appreciating that DNA satellites are both ubiquitous and universally fast-evolving, we hypothesized that satellite DNA turnover spurs evolution of DNA-protein crosslink repair beyondD. melanogaster. This hypothesis predicts pervasive Spartan gene family diversification across the Drosophila phylogeny. To study the evolutionary history of the Drosophila Spartan gene family, we conducted population genetic, molecular evolution, phylogenomic, and tissue-specific expression analyses. We uncovered widespread signals of positive selection across multiple Spartan family genes and across multiple evolutionary timescales. We also detected recurrent Spartan family gene duplication, divergence, and gene loss. Finally, we found that ovary-enriched parent genes consistently birthed testis-enriched daughter genes. To account for Drosophila-wide, Spartan family diversification, we introduce a mechanistic model of antagonistic coevolution that links DNA satellite evolution and adaptive regulation of Spartan protease activity. This framework, combined with a recent explosion of genome assemblies that encompass repeat-rich genomic regions, promises to accelerate our understanding of how DNA repeats drive recurrent evolutionary innovation to preserve genome integrity.
Differences in binding preferences for XIST partners are observed in mammals with different early pregnancy morphologies
Authors: Tsagakis Ioannis , Tinning Haidee , Malo-Estepa Irene , Whitehouse Adrian , O’Connell Mary J. , Forde Niamh , Aspden Julie L 
Published: October 2023

ABSTRACTIn comparison to protein-coding genes, long non-coding RNAs (lncRNAs) are poorly conserved between species at the sequence level yet they often perform conserved and essential regulatory roles. The lncRNAXISTmediates X chromosome inactivation (XCI) through the interaction of numerous proteins, most of which bind to its repeat regions. WhilstXISTis present across placental mammals, its sequence is divergent. In addition, the timing and mechanistic details of the process of XCI also vary across placental mammals. Here, we sought to determine whetherXISTinteractor proteins previously identified in a model mammalian species (mouse) also bind in other mammals which exhibit divergent timing of XCI (human and bovine) and differing pre-implantation embryo morphology. We show thatXISTand its putative protein partners are coordinately expressed in the endometria of mammals with different pre-implantation embryo morphologies. RNA immunoprecipitations revealed that human WTAP, SPEN, hnRNPK and CIZ1 proteins bind humanXIST. CIZ1-XISTbinding was also detected in bovine. In both human and cow, we found CIZ1 binds to the repeat E element ofXIST. However, human CIZ1 protein is not able to bind bovine repeat E, indicating a species-specific binding interaction. Together these data indicate that several of the key RNA-protein interactions withXISTare common across placental mammals, even though we observe divergence in both the RNA sequence ofXIST, and early embryo morphologies. This work sheds light upon the evolution of RNA-protein binding interactions, revealing that the binding events can be conserved even when the precise mechanism of binding has changed.Statements and DeclarationsAuthors have no financial or non-financial interests that are directly or indirectly related to the work submitted for publication.
Wireless electrocochleography in awake chinchillas: a model to study multimodal modulations at the peripheral level
Authors: Pérez-Valenzuela Catherine , Vicencio-Jiménez Sergio , Memmel Mia , Delano Paul H. , Elgueda Diego 
Published: October 2023

AbstractThe discovery and development of electrocochleography (ECochG) in animal models has been fundamental for its implementation in clinical audiology and neurotology. In our laboratory, the use of round-window ECochG recordings in chinchillas has allowed a better understanding of auditory efferent functioning. In previous works, we gave evidence of the corticofugal modulation of auditory-nerve and cochlear responses during visual attention and working memory. However, whether these cognitive top-down mechanisms to the most peripheral structures of the auditory pathway are also active during audiovisual crossmodal stimulation is unknown. Here, we introduce a new technique, wireless ECochG to record compound-action potentials of the auditory nerve (CAP), cochlear microphonics (CM), and round-window noise (RWN) in awake chinchillas during a paradigm of crossmodal (visual and auditory) stimulation. A total of four chinchillas were successfully recorded during the experimental protocol. There were non-significant differences in CAP, CM, and RWN amplitudes in response to auditory stimulation alone (clicks and tones) as compared to audio-visual crossmodal stimulation. These results suggest that cognition, such as attention or working memory, is needed for the corticofugal modulation of auditory-nerve and cochlear responses. In addition, we introduce the use of wireless ECochG in animal models as a useful tool for translational research.
Hog1 acts in a Mec1-independent manner to counteract oxidative stress following telomerase inactivation
Authors: Zeinoun Bechara , Teixeira Maria Teresa , Barascu Aurélia 
Published: October 2023

AbstractReplicative senescence is triggered when telomeres reach critically short length and activate permanent DNA damage checkpoint-dependent cell cycle arrest. Mitochondrial dysfunction and increase in oxidative stress are both features of replicative senescence in mammalian cells. Here, we show that reactive oxygen species (ROS) levels increase in the telomerase-negative cells ofSaccharomyces cerevisiaeduring replicative senescence, and that this coincides with the activation of Hog1, a mammalian p38 mitogen-activated protein kinase (MAPK) ortholog. Hog1 activation is dependent on Pbs2, the MAPK kinase (MAPKK) in its canonical pathway, and counteracts increased ROS levels during replicative senescence. While Hog1 deletion accelerates replicative senescence, we found this could stem from decreased telomere length and reduced cell viability prior to telomerase inactivation. ROS levels also increase upon telomerase inactivation when Mec1, the yeast ortholog of ATR, is mutated, suggesting that oxidative stress is not simply a consequence of DNA damage checkpoint activation in budding yeast. We speculate that oxidative stress is a conserved hallmark of telomerase-negative eukaryote cells, and that its sources and consequences can be dissected inS. cerevisiae.
Proximal protein landscapes of the type I interferon signaling cascade reveal negative regulation by the E3 ubiquitin ligase PJA2
Authors: Schiefer Samira , Hale Benjamin G. 
Published: October 2023

AbstractDeciphering the intricate dynamic events governing type I interferon (IFN) signaling is critical to unravel key regulatory mechanisms in host antiviral defense. Here, we leveraged TurboID-based proximity labeling coupled with affinity purification-mass spectrometry to comprehensively map the proximal proteomes of all seven canonical human type I IFN signaling cascade members under basal and IFN-stimulated conditions. This established a network of 103 proteins in close proximity to the core members IFNAR1, IFNAR2, JAK1, TYK2, STAT1, STAT2, and IRF9. We validated several known constitutive protein assemblies, while also revealing novel stimulus-dependent and -independent associations between key signaling molecules. Functional screening further identified PJA2 as a negative regulator of IFN signaling via its E3 ubiquitin ligase activity. Mechanistically, PJA2 interacts with the Janus kinases, TYK2 and JAK1, and promotes their non-lysine and non-degradative ubiquitination, resulting in restrained downstream STAT signaling. Our high-resolution proximal protein landscapes provide global insights into the type I IFN signaling network, and serve as a valuable resource for future exploration of its functional complexities.
Impairment of the glial phagolysosomal system drives prion-like propagation in aDrosophilamodel of Huntington’s disease
Authors: Davis Graham H. , Zaya Aprem , Panning Pearce Margaret M. 
Published: October 2023

ABSTRACTProtein misfolding, aggregation, and spread through the brain are primary drivers of neurodegenerative diseases pathogenesis. Phagocytic glia are responsible for regulating the load of pathogenic protein aggregates in the brain, but emerging evidence suggests that glia may also act as vectors for aggregate spread. Accumulation of protein aggregates could compromise the ability of glia to eliminate toxic materials from the brain by disrupting efficient degradation in the phagolysosomal system. A better understanding of phagocytic glial cell deficiencies in the disease state could help to identify novel therapeutic targets for multiple neurological disorders. Here, we report that mutant huntingtin (mHTT) aggregates impair glial responsiveness to injury and capacity to degrade neuronal debris in male and female adultDrosophilaexpressing the gene that causes Huntington’s disease (HD). mHTT aggregate formation in neurons impairs engulfment and clearance of injured axons and causes accumulation of phagolysosomes in glia. Neuronal mHTT expression induces upregulation of key innate immunity and phagocytic genes, some of which were found to regulate mHTT aggregate burden in the brain. Finally, a forward genetic screen revealed Rab10 as a novel component of Draper-dependent phagocytosis that regulates mHTT aggregate transmission from neurons to glia. These data suggest that glial phagocytic defects enable engulfed mHTT aggregates to evade lysosomal degradation and acquire prion-like characteristics. Together, our findings reveal new mechanisms that enhance our understanding of the beneficial and potentially harmful effects of phagocytic glia in HD and potentially other neurodegenerative diseases.SIGNIFICANCE STATEMENTDeposition of amyloid aggregates is strongly associated with neurodegenerative disease progression and neuronal cell loss. Many studies point to glial cells as dynamic mediators of disease, capable of phagocytosing toxic materials, but also promoting chronic inflammation and proteopathic aggregate spread. Thus, glia have emerged as promising therapeutic targets for disease intervention. Here, we demonstrate in aDrosophilamodel of Huntington’s disease that neuronal mHTT aggregates interfere with glial phagocytic engulfment, phagolysosomal processing, and innate immunity transcriptional responses. We also identify Rab10 as a novel modifier of prion-like transmission of mHTT aggregates. Our findings add to a growing narrative of glia as double-edged players in neurodegenerative diseases.
The role of location propagation for translocon complex relocation during eukaryogenesis
Authors: Carilo Isaac , Senju Yosuke , Robinson Robert C. 
Published: October 2023

ABSTRACTIn all domains of life, the translationally-active ribosome-translocon complex inserts nascent transmembrane proteins into, and processes and transports signal peptide-containing proteins across, membranes1,2. Eukaryotic translocons are anchored in the endoplasmic reticulum, while the prokaryotic complexes reside in cell membranes. DNA sequence analyses indicate that the eukaryotic Sec61/OST/TRAP translocon is inherited from an Asgard archaea ancestor3,4. However, the mechanism for translocon migration from a peripheral membrane to an internal cellular compartment (the proto-endoplasmic reticulum) during eukaryogenesis is unknown. Here we show that Asgard and eukaryotic ribosome-translocon complexes are intercompatible. We find that fluorescently-tagged Asgard translocon proteins fromCandidatusPrometheoarchaeum syntrophicum strain MK-D15, a Lokiarchaeon confirmed to contain no internal cellular membranes, are targeted to the eukaryotic endoplasmic reticulum on ectopic expression. Our data demonstrate that the location of existing ribosome-translocon complexes, at the protein level, determines the future placement of yet to be translated translocon subunits. This principle predicts that during eukaryogenesis, under positive selection pressure, the relocation of a few translocon complexes to the proto-endoplasmic reticulum will have propagated the new translocon location, leading to their loss from the cell membrane.
Chimpanzees and bonobos reinstate an interrupted triadic game
Authors: Heesen Raphaela , Bangerter Adrian , Zuberbühler Klaus , Iglesias Katia , Rossano Federico , Guéry Jean-Pascal , Genty Emilie 
Published: October 2023

AbstractWhen humans engage in joint action, they seem to so with an underlying sense of joint commitment, a feeling of mutual obligation towards their partner and a shared goal. Whether our closest living relatives, bonobos and chimpanzees, experience and understand joint commitment in the same way is subject to debate. Crucial evidence concerns how participants respond to interruptions of joint actions, particularly if they protest or attempt to reengage their reluctant or distracted partners. During dyadic interactions, bonobos and chimpanzees appear to have some sense of joint commitment, according to recent studies. Yet, data are inconsistent for triadic games with objects. We addressed this issue by engagingN=23 apes (5 adult chimpanzees, 5 infant bonobos, 13 adult bonobos) in a “tug-of-war” game with a human experimenter who abruptly stopped playing. Adult apes readily attempted to reengage the experimenter (>60% of subjects on first trial), with no group differences in the way of reengagement. Infant bonobos rarely reengaged and never did so on their first trial. Importantly, when infants reengaged passive partners, they mostly deployed (tactile) signals, yet rarely game-related behaviours (GRBs) as commonly observed in adults. These findings might explain negative results of earlier research. Bonobos and chimpanzees may thus have motivational foundations for joint commitment, although this capacity might develop over lifetime. We discuss this finding in relation to evolutionary and developmental theories on joint commitment.