bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells
Authors: Nasif Sofia , Colombo Martino , Uldry Anne-Christine , Schröder Markus S. , de Brot Simone , Mühlemann Oliver 
Published: March 2023

AbstractNonsense-mediated mRNA decay (NMD) is a eukaryotic RNA degradation pathway that targets for degradation faulty mRNAs with premature termination codons as well as many physiological mRNAs encoding full-length proteins. Consequently, NMD functions in both, quality control and post-transcriptional regulation of gene expression, and it has been implicated in the modulation of cancer progression. To investigate the role of NMD in cancer, we knocked out SMG7 in the HT1080 human fibrosarcoma cell line. SMG7 is involved in deadenylation-coupled exonucleolytic mRNA decay, one of the two main degradation pathways in mammalian NMD. Genome-wide proteomic and transcriptomic analyses confirmed that NMD is severely compromised in these SMG7-knockout HT1080 cells. We compared the oncogenic properties between the parental, the SMG7-knockout, and a rescue cell line in which we re-introduced both isoforms of SMG7. In parallel, we tested the effect of a drug inhibiting the NMD factor SMG1 on the HT1080 cells to distinguish NMD-dependent effects from putative NMD-independent functions of SMG7. Using cell-based assays as well as a mouse xenograft tumor model, we show that the oncogenic properties of the parental HT1080 cells are severely compromised when NMD is inhibited. Molecular pathway analysis revealed a strong reduction of the matrix metalloprotease 9 (MMP9) gene expression in NMD-suppressed cells. Since MMP9 expression promotes cancer cell migration and invasion, metastasis and angiogenesis, its downregulation in NMD-suppressed cells explains, at least partially, their reduced tumorigenicity. Collectively, our findings emphasize the therapeutic potential of NMD inhibition for the treatment of certain types of cancer.SignificanceNonsense-mediated mRNA decay (NMD) is a eukaryotic RNA decay pathway with reported roles in regulating cellular stress responses, differentiation, and viral defense. NMD has also emerged as a modulator of cancer progression, however, the available evidence supports both, a tumor suppressor as well as a pro-tumorigenic role for NMD. We discovered that NMD inhibition results in impaired tumorigenicity in the HT1080 human fibrosarcoma cell line and uncovered a direct correlation between NMD activity and the expression levels the pro-tumorigenic gene MMP9. Restoring MMP9 expression in NMD-suppressed cells partially improved their oncogenic properties. These results show that the tumorigenicity of the HT1080 fibrosarcoma cells relies on NMD activity and highlights the potential use of NMD inhibition as a therapeutic approach.
Widespread PRC barrel proteins play critical roles in archaeal cell division
Authors: Zhao Shan , Makarova Kira S , Zheng Wenchao , Liu Yafei , Zhan Le , Wan Qianqian , Gong Han , Krupovic Mart , Lutkenhaus Joe , Chen Xiangdong , Koonin Eugene V , Du Shishen 
Published: March 2023

AbstractCell division is fundamental to all cellular life. Most of the archaea employ one of two alternative division machineries, one centered around the prokaryotic tubulin homolog FtsZ and the other around the endosomal sorting complex required for transport (ESCRT). However, neither of these mechanisms has been thoroughly characterized in archaea. Here, we show that three of the four PRC (Photosynthetic Reaction Center) barrel domain proteins ofHaloferax volcanii(renamedCelldivisionproteins B1/2/3 (CdpB1/2/3)), play important roles in division. CdpB1 interacts directly with the FtsZ membrane anchor SepF and is essential for division, whereas deletion ofcdpB2andcdpB3causes a major and a minor division defect, respectively. Orthologs of CdpB proteins are also involved in cell division in other haloarchaea. Phylogenetic analysis shows that PRC barrel proteins are widely distributed among archaea, including the highly conserved CdvA protein of the crenarchaeal ESCRT-based division system. Thus, diverse PRC barrel proteins appear to be central to cell division in most if not all archaea. Further study of these proteins is expected to elucidate the division mechanisms in archaea and their evolution.
Deep Active Learning for Robust Biomedical Segmentation
Authors: Arikan Mustafa , Sallo Ferenc , Montesel Andrea , Ahmed Hend , Hagag Ahmed , Book Marius , Faatz Henrik , Cicinelli Maria , Meshkinfamfard Sepehr , Ongun Sevim , Dubis Adam , Lilaonitkul Watjana 
Published: March 2023

AbstractDeep learning for medical applications faces many unique challenges. A major challenge is the large amount of labelled data for training, while working in a relatively data scarce environment. Active learning can be used to overcome the vast data need challenge. A second challenged faced is poor performance outside of a experimental setting, contrary to the high requirement for safety and robustness. In this paper, we present a novel framework for estimating uncertainty metrics and incorporating a similarity measure to improve active learning strategies. To showcase effectiveness, a medical image segmentation task was used as an exemplar. In addition to faster learning, robustness was also addressed through adversarial perturbations. Using epistemic uncertainty and our framework, we can cut number of annotations needed by 39% and by 54% using epistemic uncertainty and a similarity metric.
Inclusion, reporting and analysis of demographic variables in chronobiology and sleep research
Authors: Tir Selma , White Rhiannon , Spitschan Manuel 
Published: March 2023

AbstractMany aspects of sleep and circadian physiology appear to be sensitive to participant-level characteristics. While recent research robustly highlights the importance of considering participant-level demographic information, it is not clear to what extent this information is available within the large body of existing literature. This article investigates study sample characteristics within the published sleep and chronobiology research over the past 40 years. 6,777 articles were identified and a random sample of 20% was included. The reporting of sample size, age, sex, gender, ethnicity, level of education, socio-economic status, and profession of the study population was scored, and any reported aggregate summary statistics for these variables were recorded. We found that while >90% of studies reported age or sex, all other variables were reported in <25% of cases. Reporting quality was highly variable, indicating an opportunity to standardize reporting guidelines for participant-level characteristics to facilitate meta analyses.SummaryIn this article, we address the question of how representative, diverse and inclusive are published articles in sleep and chronobiology research. We analyzed a sample of >1300 articles published in sleep and chronobiology journals between 1979 and 2019 for its inclusion, reporting and analysis of study population characteristics, including age, sex, gender, race/ethnicity, level of education, socio-economic status, and profession. We found that while >90% of studies reported age or sex, all other variables were reported in <25% of cases, with the frequency of reporting changing over time. We identify opportunities for improving the reporting of demographic variables.Research AgendaFuture research needs to: 1. Establish schemas for reporting demographic variables in a harmonized way across geographical and cultural contexts; 2. Identify gaps in the sleep and chronobiology literature with respect to understudied populations; 3. Understand the extent to which research practices allow for the inclusion of diverse populations in all stages of the research cycle, and how this can exacerbate health inequities.Practice PointsPublished studies on circadian and sleep physiology should be carefully examined.Reporting of demographic variables should be done deliberately and systematically.Inclusion and diversity of different populations across the field needs to be ensured.
Basal forebrain activity predicts functional degeneration in the entorhinal cortex and decreases with Alzheimer’s Disease progression
Authors: Mieling Marthe , Göttlich Martin , Yousuf Mushfa , Bunzeck Nico ,   the Alzheimer’s Disease Neuroimaging Initative
Published: March 2023

AbstractBACKGROUND AND OBJECTIVESRecent models of Alzheimer’s Disease (AD) suggest the nucleus basalis of Meynert (NbM) as the origin of structural degeneration followed by the entorhinal cortex (EC). However, the functional properties of NbM and EC regarding amyloid-β and hyperphosphorylated tau remain unclear.METHODSWe analyzed resting-state (rs)fMRI data with CSF assays from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n=71) at baseline and two years later.RESULTSAt baseline, local activity, as quantified by fractional amplitude of low-frequency fluctuations (fALFF), differentiated between normal and abnormal CSF groups in the NbM but not EC. Further, NbM activity linearly decreased as a function of CSF ratio, resembling the disease status. Finally, NbM activity predicted the annual percentage signal change in EC, but not the reverse, independent from CSF ratio.DISCUSSIONOur findings give novel insights into the pathogenesis of AD by showing that local activity in NbM is affected by proteinopathology and predicts functional degeneration within the EC.
Conversion of methionine biosynthesis inE. colifrom trans- to direct-sulfurylation enhances extracellular methionine levels
Authors: Gruzdev Nadya , Hacham Yael , Haviv Hadar , Stern Inbar , Gabay Matan , Bloch Itai , Amir Rachel , Gal Maayan , Yadid Itamar 
Published: March 2023

AbstractMethionine is an essential amino acid in mammals and a critical metabolite in all organisms. As such, various applications, including food, feed, and pharmaceuticals, necessitate the addition of L-methionine. Although amino acids and other metabolites are commonly produced through bacterial fermentation, high-yield biosynthesis of L-methionine remains a significant challenge due to the strict cellular regulation of the biosynthesis pathway. As a result, methionine is produced primarily synthetically, resulting in a racemic mixture of D,L-methionine. This study aimed to enhance methionine bio-production yields inE. coliby replacing its highly regulated trans-sulfurylation pathway with the more common direct-sulfurylation pathway used by other bacteria. To this end, we generated an auxotrophE. colistrain (MG1655) by simultaneously deletingmetAandmetBgenes and complementing them withmetXandmetYfrom different bacteria. Complementation of the genetically modifiedE. coliwithmetX/metYfromCyclobacterium marinumorDeinococcus geothermalis, together with the deletion of the global repressormetJand overexpression of the transporter YjeH, resulted in a substantial increase of up to 126 and 160-fold methionine relative to the wild-type strain, respectively, and accumulation of up to 700 mg/L using minimal MOPS medium and 2 ml culture. Our findings provide a method to study methionine biosynthesis and a chassis for enhancing L-methionine production by fermentation.HighlightsReplacement ofE. coli metAandmetBwithmetXandmetYrecovered its growthThe engineeredE. colihas a 160-fold increase in extracellular methionine levelsSelection of differentmetXandmetYleads to varying growth rates and enhanced methionine levels
Sensory neuron LKB1 mediates ovarian and reproductive function
Authors: Lenert Melissa E , Burton Michael D 
Published: March 2023

AbstractTreatments for reproductive disorders in women primarily consist of hormone replacement therapy, which can have negative health impacts. Bidirectional communication between sensory neurons and innervated organs is an emerging area of interest in tissue physiology with potential relevance for reproductive disorders. Indeed, the metabolic activity of sensory neurons can have profound effects on reproductive phenotypes. To investigate this phenomenon, we utilized a murine model with conditional deletion in sensory neurons of liver kinase B1 (LKB1), a serine/threonine kinase that regulates cellular metabolism. Female mice with this LKB1 deletion (Nav1.8cre;LKB1fl/fl) had significantly more pups per litter compared to wild-type females. Interestingly, the LKB1 genotype of male breeders had no effect on fertility outcomes, thus indicating a female-specific role of sensory neuron metabolism in fertility. LKB1 deletion in sensory neurons resulted in reduced ovarian innervation from dorsal root ganglia neurons and increased follicular turnover compared to littermate controls. In summary, LKB1 expression in peripheral sensory neurons plays an important role in modulating fertility of female mice via ovarian sensory innervation.
Ground-truth validation of uni- and multivariate lesion inference approaches
Authors: Zavaglia Melissa , Malherbe Caroline , Schlaadt Sebastian , Nachev Parashkev , Hilgetag Claus C 
Published: March 2023

AbstractLesion analysis aims to reveal causal contributions of brain regions to brain functions. Various strategies have been used for such lesion inferences. These approaches can be broadly categorized as univariate or multivariate methods. Here we analysed data from 581 patients with acute ischemic injury, parcellated into 41 Brodmann areas, and systematically investigated the inferences made by two univariate and two multivariate lesion analysis methods via ground-truth simulations, in which we defined a priori contributions of brain areas to assumed brain function. Particularly, we analysed single-region models, with only single areas presumed to contribute functionally, and multiple-region models, with two contributing regions that interacted in a synergistic, redundant or mutually inhibitory mode. The functional contributions could vary in proportion to the lesion damage or in a binary way. The analyses showed a considerably better performance of the tested multivariate than univariate methods in terms of accuracy and mis-inference error. Specifically, the univariate approaches of Lesion Symptom Mapping (LSM) as well as Lesion Symptom Correlation (LSC) mis-inferred substantial contributions from several areas even in the single-region models, and also after accounting for lesion size. By contrast, the multivariate approaches of Multi- Area Pattern Prediction (MAPP), which is based on machine learning, and Multi-perturbation Shapley value Analysis (MSA), based on coalitional game theory, delivered consistently higher accuracy and specificity. Our findings suggest that the tested multivariate approaches produce largely reliable lesion inferences, without requiring lesion size consideration, while the application of the univariate methods may yield substantial mis-localizations that limit the reliability of functional attributions.
Visual integration of omics data to improve 3D models of fungal chromosomes
Authors: Poinsignon Thibault , Gallopin Mélina , Grognet Pierre , Malagnac Fabienne , Lelandais Gaëlle , Poulain Pierre 
Published: March 2023

AbstractThe functions of eukaryotic chromosomes and their spatial architecture in the nucleus are reciprocally dependent. Hi-C experiments are routinely used to study chromosome 3D organization by probing chromatin interactions. Standard representation of the data has relied on contact maps that show the frequency of interactions between parts of the genome. In parallel, it has become easier to build 3D models of the entire genome based on the same Hi-C data, and thus benefit from the methodology and visualization tools developed for structural biology. 3D modeling of entire genomes leverages the understanding of their spatial organization. However, this opportunity for original and insightful modeling is under exploited. In this paper, we show how seeing the spatial organization of chromosomes can bring new perspectives to Hi-C data analysis. We assembled state-of-the-art tools into a workflow that goes from Hi-C raw data to fully annotated 3D models and we re-analysed public Hi-C datasets available for three fungal species. Besides the well-described properties of the spatial organization of their chromosomes (Rabl conformation, hypercoiling and chromosome territories), our 3D models highlightedi)inSaccharomyces cerevisiae, the backbones of the cohesin anchor regions, which were aligned all along the chromosomes,ii)inSchizosaccharomyces pombe, the oscillations of the coiling of chromosome arms throughout the cell cycle andiii)inNeurospora crassa, the massive relocalization of histone marks in mutants of heterochromatin regulators. 3D modeling of the chromosomes brings new opportunities for visual integration. This holistic perspective supports intuition and lays the foundation for building new concepts.
Parallel loss of type VI secretion systems in two multi-drug resistantEscherichia colilineages
Authors: Cummins Elizabeth A. , Moran Robert A. , Snaith Ann E. , Hall Rebecca J. , Connor Chris H. , Dunn Steven J. , McNally Alan 
Published: March 2023

AbstractThe repeated emergence of multi-drug resistant (MDR)Escherichia coliclones is a threat to public health globally. In recent work, drug resistantE. coliwere shown to be capable of displacing commensalE. coliin the human gut. Given the rapid colonisation observed in travel studies, it is possible that the presence of a type VI secretion system (T6SS) may be responsible for the rapid competitive advantage of drug resistantE. coliclones. We employed large scale genomic approaches to investigate this hypothesis. First, we searched for T6SS genes across a curated dataset of over 20,000 genomes representing the full phylogenetic diversity ofE. coli. This revealed large, non-phylogenetic variation in the presence of T6SS genes. No association was found between T6SS gene carriage and MDR lineages. However, multiple clades containing MDR clones have lost essential structural T6SS genes. We characterised the T6SS loci of ST410 and ST131 and identified specific recombination and insertion events responsible for the parallel loss of essential T6SS genes in two MDR clones.Data SummaryThe genome sequence data generated in this study is publicly available from NCBI under BioProject PRJNA943186, alongside a complete assembly in GenBank under accessionsCP120633-CP120634. All other sequence data used in this paper has been taken from ENA with the appropriate accession numbers listed within the methods section. TheE. coligenome data sets used in this work are from a previous publication, the details of which can be found in the corresponding supplementary data files 10.6084/m9.figshare.21360108 [1].Impact StatementEscherichia coliis a globally significant pathogen that causes the majority of urinary tract infections. Treatment of these infections is exacerbated by increasing levels of drug resistance. Pandemic multi-drug resistant (MDR) clones, such as ST131-C2/H30Rx, contribute significantly to global disease burden. MDRE. coliclones are able to colonise the human gut and displace the resident commensalE. coli. It is important to understand how this process occurs to better understand why these pathogens are so successful. Type VI secretion systems may be one of the antagonistic systems employed byE. coliin this process. Our findings provide the first detailed characterisation of the T6SS loci in ST410 and ST131 and shed light on events in the evolutionary pathways of the prominent MDR pathogens ST410-B4/H42RxC and ST131-C2/H30Rx.
Prediction of G4 formation in live cells with epigenetic data: a deep learning approach
Authors: Korsakova Anna , Phan Anh Tuân 
Published: March 2023

ABSTRACTG-quadruplexes (G4s) are secondary structures abundant in DNA that may play regulatory roles in cells. Despite the ubiquity of the putative G-quadruplex sequences (PQS) in the human genome, only a small fraction forms secondary structures in cells. Folded G4, histone methylation and chromatin accessibility are all parts of the complexcisregulatory landscape. We propose an approach for G4 formation prediction in cells that incorporates epigenetic and chromatin accessibility data. The novel approach termedepiG4NNefficiently predicts cell-specific G4 formation in live cells based on a local epigenomic snapshot. Our architecture confirms the close relationship between H3K4me3 histone methylation, chromatin accessibility and G4 structure formation. Trained on A549 cell data,epiG4NNwas then able to predict G4x formation in HEK293T and K562 cell lines. We observe the dependency of model performance with different epigenetic features on the underlying experimental condition of G4 detection. We expect that this approach will contribute to the systematic understanding of correlations between structural and epigenomic feature landscape.
Mathematical modeling suggests cytotoxic T lymphocytes control growth of B16 tumor cells in collagin-fibrin gels by cytolytic and non-lytic mechanisms
Authors: Majumder Barun , Budhu Sadna , Ganusov Vitaly V. 
Published: March 2023

AbstractCytotoxic T lymphocytes (CTLs) are important in controlling some viral infections, and therapies involving transfer of large numbers of cancer-specific CTLs have been successfully used to treat several types of cancers in humans. While molecular mechanisms of how CTLs kill their targets are relatively well understood we still lack solid quantitative understanding of the kinetics and efficiency at which CTLs kill their targets in different conditions. Collagen-fibrin gel-based assays provide a tissue-like environment for the migration of CTLs, making them an attractive system to study the cytotoxicity in vitro. Budhuet al.[1] systematically varied the number of peptide (SIINFEKL)- pulsed B16 melanoma cells and SIINFEKL-specific CTLs (OT-1) and measured remaining targets at different times after target and CTL co-inoculation into collagen-fibrin gels. The authors proposed that their data were consistent with a simple model in which tumors grow exponentially and are killed by CTLs at a per capita rate proportional to the CTL density in the gel. By fitting several alternative mathematical models to these data we found that this simple “exponential-growth-mass-action-killing” model does not precisely fit the data. However, determining the best fit model proved difficult because the best performing model was dependent on the specific dataset chosen for the analysis. When considering all data that include biologically realistic CTL concentrations (E≤ 107cell/ml) the model in which tumors grow exponentially and CTLs suppress tumor’s growth non-lytically and kill tumors according to the mass-action law (SiGMA model) fitted the data with best quality. Results of power analysis suggested that longer experiments (∼ 3 − 4 days) with 4 measurements of B16 tumor cell concentrations for a range of CTL concentrations would best allow to discriminate between alternative models. Taken together, our results suggest that interactions between tumors and CTLs in collagen-fibrin gels are more complex than a simple exponential-growth- mass-action killing model and provide support for the hypothesis that CTLs impact on tumors may go beyond direct cytotoxicity.
The immune response to a fungus in pancreatic cancer samples
Authors: Brayer KJ , Hanson JA , Cingam S , Martinez C , Ness SA , Rabinowitz I 
Published: March 2023

AbstractPancreatic ductal adenocarcinoma (PDAC) is a poor prognosis cancer with an .aggressive growth profile that is often diagnosed at late stage and that has few curative or therapeutic options. PDAC growth has been linked to alterations in the pancreas microbiome, which could include the presence of the fungusMalassezia. We used RNA-sequencing to compare 14 paired tumor and normal (tumor adjacent) pancreatic cancer samples and foundMalasseziaRNA in both the PDAC and normal tissues. Although the presence ofMalasseziawas not correlated with tumor growth, a set of immune- and inflammatory-related genes were up-regulated in the PDAC compared to the normal samples, suggesting that they are involved in tumor progression. Gene set enrichment analysis suggests that activation of the complement cascade pathway and inflammation could be involved in pro PDAC growth.