bluuebunny/crossref_metadata_2025_split huggingface dataset:
ETS1, a target gene of the EWSR1::FLI1 fusion oncoprotein, regulates the expression of the focal adhesion protein TENSIN3
Authors: Ebegboni Vernon Justice , Jones Tamara L. , Brownmiller Tayvia , Zhao Patrick X. , Pehrsson Erica C. , Sundara Rajan Soumya , Caplen Natasha J. 
Published: December 2023

AbstractThe mechanistic basis for the metastasis of Ewing sarcomas remains poorly understood, as these tumors harbor few mutations beyond the chromosomal translocation that initiates the disease. Instead, the epigenome of Ewing sarcoma (EWS) cells reflects the regulatory state of genes associated with the DNA binding activity of the fusion oncoproteins EWSR1::FLI1 or EWSR1::ERG. In this study, we examined the EWSR1::FLI1/ERG’s repression of transcription factor genes, concentrating on those that exhibit a broader range of expression in tumors than in EWS cell lines. Focusing on one of these target genes,ETS1, we detected EWSR1::FLI1 binding and an H3K27me3 repressive mark at this locus. Depletion of EWSR1::FLI1 results in ETS1’s binding of promoter regions, substantially altering the transcriptome of EWS cells, including the upregulation of the gene encoding TENSIN3 (TNS3), a focal adhesion protein. EWS cell lines expressing ETS1 (CRISPRa) exhibited increased TNS3 expression and enhanced movement compared to control cells. The cytoskeleton of control cells and ETS1-activated EWS cell lines also differed. Specifically, control cells exhibited a distributed vinculin signal and a network-like organization of F-actin. In contrast, ETS1-activated EWS cells showed an accumulation of vinculin and F-actin towards the plasma membrane. Interestingly, the phenotype of ETS1-activated EWS cell lines depleted of TNS3 resembled the phenotype of the control cells. Critically, these findings have clinical relevance asTNS3expression in EWS tumors positively correlates with that ofETS1.SignificanceETS1’s transcriptional regulation of the gene encoding the focal adhesion protein TENSIN3 in Ewing sarcoma cells promotes cell movement, a critical step in the evolution of metastasis.Graphical abstract
A novel framework to build saliva-based DNA methylation biomarkers: quantifying systemic chronic inflammation as a case study
Authors: Schmunk Lisa J. , Call Toby P. , McCartney Daniel L. , Javaid Hira , Hastings Waylon J. , Jovicevic Vanja , Kojadinović Dragoljub , Tomkinson Natacha , Zlamalova Eliska , McGee Kirsty C. , Sullivan Jack , Campbell Archie , McIntosh Andrew M , Óvári Veronika , Wishart Karl , Behrens Christian E. , Stone Emma , Gavrilov Miloš , Thompson Rob ,   Hurdle bio-infrastructure team, Jackson Thomas , Lord Janet M. , Stubbs Thomas M. , Marioni Riccardo E. , Martin-Herranz Daniel E. 
Published: December 2023

AbstractAccessible and non-invasive biomarkers that measure human ageing processes and the risk of developing age-related disease are paramount in preventative healthcare. In this study, we describe a novel framework to train saliva-based DNA methylation (DNAm) biomarkers that are reproducible and biologically interpretable. By leveraging a reliability dataset with replicates across tissues, we demonstrate that it is possible to transfer knowledge from blood DNAm data to saliva DNAm data using DNAm proxies of blood proteins (EpiScores). We then apply these methods to create a new saliva-based epigenetic clock (InflammAge) that quantifies systemic chronic inflammation (SCI) in humans. Using a large blood DNAm human cohort with linked electronic health records and over 18,000 individuals (Generation Scotland), we demonstrate that InflammAge significantly associates with all-cause mortality, disease outcomes, lifestyle factors and immunosenescence; in many cases outperforming the widely used SCI biomarker C-reactive protein (CRP). We propose that our biomarker discovery framework and InflammAge will be useful to improve our understanding of the molecular mechanisms underpinning human ageing and to assess the impact of gero-protective interventions.
Human telomere length is chromosome specific and conserved across individuals
Authors: Karimian Kayarash , Groot Aljona , Huso Vienna , Kahidi Ramin , Tan Kar-Tong , Sholes Samantha , Keener Rebecca , McDyer John F. , Alder Jonathan K. , Li Heng , Rechtsteiner Andreas , Greider Carol W. 
Published: December 2023

AbstractShort telomeres cause age-related disease and long telomeres predispose to cancer; however, the mechanisms regulating telomere length are unclear. To probe these mechanisms, we developed a nanopore sequencing method, Telomere Profiling, that is easy to implement, precise, and cost effective with broad applications in research and the clinic. We sequenced telomeres from individuals with short telomere syndromes and found similar telomere lengths to the clinical FlowFISH assay. We mapped telomere reads to specific chromosome end and identified both chromosome end-specific and haplotype-specific telomere length distributions. In the T2T HG002 genome, where the average telomere length is 5kb, we found a remarkable 6kb difference in lengths between some telomeres. Further, we found that specific chromosome ends were consistently shorter or longer than the average length across 147 individuals. The presence of conserved chromosome end-specific telomere lengths suggests there are new paradigms in telomere biology that are yet to be explored. Understanding the mechanisms regulating length will allow deeper insights into telomere biology that can lead to new approaches to disease.
Stable chromosome configuration and loop-based polarization in animal symbionts
Authors: Viehboeck Tobias , Weber Philipp M. , Krause Nicole , Varoquaux Nelle , Boccard Frédéric , Junier Ivan , Bulgheresi Silvia , Lioy Virginia S. 
Published: December 2023

ABSTRACTChromosome partitioning precedes the division of the cytoplasm, and its evolution is linked with the positioning of the division plane. So far, bacterial chromosome biology has heavily focused on transversally dividing, free-living ones. Here, we determined the chromosome organization of three longitudinally dividingNeisseriaceaeexclusively inhabiting the oral cavity of mammals. We showed that in all three multicellular bacteria the origin of DNA replication is invariably located at the host-attached (proximal) pole. Next, 3C-seq revealed loop-based folding of theoriregion inAlysiella filiformisandSimonsiella muelleri. Moreover, genes involved in cell motility, piliation and signal transduction mechanisms were specifically looped when transcriptionally and translationally active cells adhered to a substrate, but not when cultured in liquid. Overall, we propose that proximal positioning of theoriand loop-based folding of its surrounding DNA may mediate localized translation of proteins involved in host colonization.
Structure of the human systemic RNAi defective transmembrane protein 1 (hSIDT1) reveals the conformational flexibility of its lipid binding domain
Authors: Navratna Vikas , Kumar Arvind , Rana Jaimin K. , Mosalaganti Shyamal 
Published: December 2023

AbstractInC. elegans, inter-cellular transport of the small non-coding RNA causing systemic RNA interference (RNAi) is mediated by the transmembrane protein SID1, encoded by thesid1gene in the systemic RNA interference-defective (sid) loci. SID1 shares structural and sequence similarity with cholesterol uptake protein 1 (CHUP1) and is classified as a member of the cholesterol uptake family (ChUP). Although systemic RNAi is not an evolutionarily conserved process, thesidgene products are found across the animal kingdom, suggesting the existence of other novel gene regulatory mechanisms mediated by small non-coding RNAs. Human homologs ofsidgene products – hSIDT1 and hSIDT2 – mediate contact-dependent lipophilic small non-coding dsRNA transport. Here, we report the structure of recombinant human SIDT1. We find that the extra- cytosolic domain (ECD) of hSIDT1 adopts a double jelly roll fold, and the transmembrane domain (TMD) exists as two modules – a flexible lipid binding domain (LBD) and a rigid TMD core. Our structural analyses provide insights into the inherent conformational dynamics within the lipid binding domain in cholesterol uptake (ChUP) family members.
Genotypic and Phenotypic Analyses of Two Distinct Sets ofPseudomonas aeruginosaUrinary Tract Isolates
Authors: Ebrahim HA , Haldenby S , Moore MP , Dashti AA , Floyd RV , Fothergill JL 
Published: December 2023

AbstractUrinary tract infections (UTIs) are associated with a high burden of morbidity, mortality, and cost.Pseudomonas aeruginosaemploys a myriad of virulence factors, including biofilm formation and motility mechanisms, to cause infections including persistent UTIs.P. aeruginosais highly resistant to antibiotics and the World Health Organization has identified it as a pathogen for which novel antimicrobials are urgently required. Genotypic and phenotypic characterization ofP. aeruginosafrom UTIs are underreported. In addition, the rise of antimicrobial resistance (AMR) is a cause for concern, particularly in many countries where surveillance is severely lacking.22P. aeruginosaUTI isolates were sourced from the United Kingdom (UK) and Kuwait. To establish the phenotypes of UK isolates, growth analysis, biofilm formation assays, motility assays, and antibiotic disc diffusion assays were performed. Whole genome sequencing, antimicrobial susceptibility assays, andin silicodetection of AMR-associated genes were conducted on both sets of isolates.In terms of their phenotypic characteristics and genomic composition, the UTI isolates varied. Multiple resistance genes associated with resistance to various classes of antibiotics, such as aminoglycosides, fluoroquinolones, and β-lactams, particularly in isolates from Kuwait. Extreme antibiotic resistance was detected in the isolates obtained from Kuwait, indicating that the country may be an antibiotic resistance hotspot.This study highlights that isolates from UTIs are diverse and can display extremely high resistance. Surveillance in countries such as Kuwait are currently limited and this study suggest the need for greater surveillance.
Fast inhibition slows and desynchronizes mouse auditory efferent neuron activity
Authors: Fischl Matthew , Pederson Alia , Voglewede Rebecca , Cheng Hui , Drew Jordan , Cadenas Lester Torres , Weisz Catherine J.C. 
Published: December 2023

AbstractThe encoding of acoustic stimuli requires precise neuron timing. Auditory neurons in the cochlear nucleus (CN) and brainstem are well-suited for accurate analysis of fast acoustic signals, given their physiological specializations of fast membrane time constants, fast axonal conduction, and reliable synaptic transmission. The medial olivocochlear (MOC) neurons that provide efferent inhibition of the cochlea reside in the ventral brainstem and participate in these fast neural circuits. However, their modulation of cochlear function occurs over time scales of a slower nature. This suggests the presence of mechanisms that restrict MOC inhibition of cochlear function. To determine how monaural excitatory and inhibitory synaptic inputs integrate to affect the timing of MOC neuron activity, we developed a novel in vitro slice preparation (‘wedge-slice’). The wedge-slice maintains the ascending auditory nerve root, the entire CN and projecting axons, while preserving the ability to perform visually guided patch-clamp electrophysiology recordings from genetically identified MOC neurons. The ‘in vivo-like’ timing of the wedge-slice demonstrates that the inhibitory pathway accelerates relative to the excitatory pathway when the ascending circuit is intact, and the CN portion of the inhibitory circuit is precise enough to compensate for reduced precision in later synapses. When combined with machine learning PSC analysis and computational modeling, we demonstrate a larger suppression of MOC neuron activity when the inhibition occurs with in vivo-like timing. This delay of MOC activity may ensure that the MOC system is only engaged by sustained background sounds, preventing a maladaptive hyper-suppression of cochlear activity.Significance StatementAuditory brainstem neurons are specialized for speed and fidelity to encode rapid features of sound. Extremely fast inhibition contributes to precise brainstem sound encoding. This circuit also projects to medial olivocochlear (MOC) efferent neurons that suppress cochlear function to enhance detection of signals in background sound. Using a novel brain slice preparation with intact ascending circuitry, we show that inhibition of MOC neurons can also be extremely fast, with the speed of the circuit localized to the cochlear nucleus. In contrast with the enhancement of precision afforded by fast inhibition in other brainstem auditory circuits, inhibition to MOC neurons instead has a variable onset that delays and desynchronizes activity, thus reducing precision for a slow, sustained response to background sounds.
Cannabidiol improves learning and memory deficits and alleviates anxiety in 12-month-old SAMP8 Mice
Authors: Goodland Monica N. , Banerjee Subhashis , Niehoff Michael L. , Young Benjamin J. , Macarthur Heather , Butler Andrew A. , Morley John E. , Farr Susan A. 
Published: December 2023

ABSTRACTCannabidiol (CBD) has gained a lot of interest in recent years for its purported medicinal properties. CBD has been investigated for the treatment of anxiety, depression, epilepsy, neuroinflammation, and pain. Recently there has been an interest in CBD as a possible treatment for age-related disorders such as Alzheimer’s disease and related disorders (ADRD). Here we tested the hypothesis that chronic CBD administration would improve learning and memory in the SAMP8 mouse model of Alzheimer’s disease. SAMP8 mice aged 11 months (at the start of the study) were administered vehicle or CBD (3 or 30 mg/Kg) daily via oral gavage for 2 months. Vehicle-treated young SAMP8 mice (age 3 months at the start of the study) served as unimpaired controls. After 30 days of treatment (4 and 12 months of age), learning and memory, activity, anxiety, strength and dexterity were assessed. High dose CBD treatment significantly improved learning and memory of the 12-month-old mice in the T maze. Novel object recognition memory was also improved by CBD in aged CBD treated mice. Aged CBD treated mice also displayed less anxiety in the elevated plus maze test compared to controls. However, activity and strength levels were similar between groups. Biochemical analysis revealed decreased markers of oxidative stress, providing a possible mechanism by which CBD treatment impacts learning, memory, and anxiety. These results highlight the potential use of CBD as a therapeutic for age related cognitive impairment and dementia.
Cryo-EM structure of the bacterial effector protein SipA bound to F-actin reveals a unique mechanism for filament stabilization
Authors: Guo Emily Z. , Chou Steven Z. , Lara-Tejero Maria , Galán Jorge E. 
Published: December 2023

ABSTRACTThe bacterial pathogenSalmonellaspp. modulates cellular processes by delivering effector proteins through its type III secretion systems. Among these effectors, SipA facilitates bacterial invasion and promotes intestinal inflammation. The mechanisms by which this effector carries out these functions are incompletely understood, although SipA’s ability to modulate actin dynamics is central to some of these activities. Here, we report the cryo-EM structure of SipA bound to filamentous actin. The structure shows that this effector stabilizes actin filaments through unique interactions of its carboxy-terminal domain with four actin subunits. Furthermore, our structure-function studies revealed that SipA’s actin-binding activity is independent of its ability to stimulate intestinal inflammation. Overall, these studies illuminate critical aspects ofSalmonellapathogenesis and provide unique insight into the mechanisms by which a bacterial effector modulates actin dynamics.
Survivin Mediates Mitotic Onset in HeLa Cells Through Activation of the Cdk1-Cdc25B Axis
Authors: Cánovas Pedro M. 
Published: December 2023

ABSTRACTThe Survivin protein has roles in repairing incorrect microtubule-kinetochore attachments at prometaphase and the faithful execution of cytokinesis, both as part of thechromosomalpassengercomplex(CPC) (1). In this context, errors frequently lead to aneuploidy, polyploidy and cancer (1). Adding to these well-known roles of this protein, this paper now shows for the first time that Survivin is required for cancer cells to enter mitosis, and that, in its absence, HeLa cells accumulate at early prophase, or prior to reported before (2, 3). The early prophase blockage in cells lacking Survivin is demonstrated by the presence of an intact nuclear lamina and low Cdk1 activity (4). Interestingly, Survivin and Cdk1 form a complexin vivo. This interaction peaks at mitosis, and its molecular targeting indicates that Survivin is needed for Cdk1 to be active. In this regard, escaping the blockage induced by Survivin abrogation leads to multiple mitotic defects, ormitotic catastrophe, and eventually cell death. Mechanistically, recombinant Survivin can induce the activation of Cdk1 via Cdc25in vitro. Coincidentally, Cdk1 mislocalizes at the centrosome when Survivin is not expressed. Moreover, Survivin directly interacts with phosphatase Cdc25B, bothin vitroandin vivo, and in the absence of the former, an inactive cytosolic Cdc25B-Cdk1-Cyclin B1 complex accumulates, which coincides with the mitotic arrest induced by Survivin depletion. Finally, in agreement with a role for Survivin in the early activation of Cdk1, the G2/early prophase accumulation induced in HeLa cells by Survivin abrogation could be bypassed by a gain-of-function Cdc25B mutant, which drove cells into mitosis.
Supervised contrastive learning enhances MHC-II peptide binding affinity prediction
Authors: Shen Long-Chen , Liu Yan , Liu Zi , Zhang Yumeng , Wang Zhikang , Guo Yuming , Rossjohn Jamie , Song Jiangning , Yu Dong-Jun 
Published: December 2023

AbstractAccurate prediction of major histocompatibility complex (MHC)-peptide binding affinity can improve our understanding of cellular immune responses and guide personalized immunotherapies. Nevertheless, the existing deep learning-based approaches for predicting MHC-II peptide interactions fall short of satisfactory performance and offer restricted model interpretability. In this study, we propose a novel deep neural network, termed ConBoTNet, to address the above issues by introducing the designed supervised contrastive learning and bottleneck transformer extractors. Specifically, the supervised contrastive learning pre-training enhances the model’s representative and generalizable capabilities on MHC-II peptides by pulling positive pairs closer and pushing negative pairs further in the feature space, while the bottleneck transformer module focuses on MHC-II peptide interactions to precisely identify binding cores and anchor positions in an unsupervised manner. Extensive experiments on benchmark datasets under 5-fold cross-validation, leave-one-molecule-out validation, independent testing, and binding core prediction settings highlighted the superiority of our proposed ConBoTNet over current state-of-the-art methods. Data distribution analysis in the latent feature space demonstrated that supervised contrastive learning can aggregate MHC-II-peptide samples with similar affinity labels and learn common features of similar affinity. Additionally, we interpreted the trained neural network by associating the attention weights with peptides and innovatively find both well-established and potential peptide motifs. This work not only introduces an innovative tool for accurately predicting MHC-II peptide affinity, but also provides new insights into a new paradigm for modeling essential biological interactions, advancing data-driven discovery in biomedicine.
Transcription near arrested DNA replication forks triggers ribosomal DNA copy number changes
Authors: Sasaki Mariko , Kobayashi Takehiko 
Published: December 2023

SUMMARYDNA copy number changes as a consequence of chromosomal structural rearrangements or the production of extrachromosomal circular DNA. Here, we demonstrate that the histone deacetylase Sir2 maintains the copy number of budding yeast ribosomal RNA gene (rDNA) by suppressing the initiation of homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs) that are formed upon DNA replication fork arrest in the rDNA. Sir2 represses the transcription from the regulatory promoter E-pro, which is located near the fork arresting site. When Sir2 is absent, transcription is stimulated by E-pro but terminated by arrested replication forks. This transcription–replication collision enhances DSB formation and induces DSB end resection and HR-mediated repair that is prone to chromosomal rDNA copy number changes and the production of extrachromosomal rDNA circles. Therefore, repression of transcription near arrested replication forks is critical for the maintenance of genome stability by directing DSB repair into the HR-independent, rearrangement-free pathway.
Species interactions drive continuous assembly of freshwater communities in stochastic environments
Authors: Tabi Andrea , Siqueira Tadeu , Tonkin Jonathan D. 
Published: December 2023

AbstractUnderstanding the factors driving the maintenance of long-term biodiversity in changing environments is essential for improving restoration and sustainability strategies in the face of global environmental change. Biodiversity is shaped by both niche and stochastic processes, however the strength of deterministic processes in unpredictable environmental regimes is highly debated. Since communities continuously change over time and space — species persist, disappear or (re)appear — understanding the drivers of species gains and losses from communities should inform us about whether niche or stochastic processes dominate community dynamics. Applying a nonparametric causal discovery approach to a 30-year time series containing annual abundances of benthic invertebrates across 66 locations in New Zealand rivers, we found a strong asynchronous causal relationship between species gains and losses directly driven by predation indicating that niche processes dominate community dynamics. Despite the unpredictable nature of these system, environmental noise was only indirectly related to species gains and losses through altering life history trait distribution. Using a stochastic birth-death framework, we demonstrate that the negative relationship between species gains and losses can not emerge without strong niche processes. Our results showed that even in systems that are dominated by unpredictable environmental variability, species interactions drive continuous community assembly.