bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chromatin Remodeling and Epigenetic Modifications in Planar Cell Migration
Authors: Forman Jack , Hine Briar , Kaonis Samantha , Ghosh Soham 
Published: December 2023

ABSTRACTThe cell nucleus plays a critical role in cell migration by its deformability under forces, by acting as a piston that activates mechanosensitive channels, and also by serving as a ruler tailoring cell response to spatial constraints. Cell nuclear mechanics determine the mechanobiology of static and migrating cells. Here, we report that intranuclear chromatin architecture plays a previously unknown role during cell migration on planar substrates. By inhibiting histone deacetylation, which compacts chromatin, and a methyltransferase, which affects chromatin remodeling and chromatin compaction, we showed that cell migration speed and persistence drastically slowed wound closure efficiency in an in vitro scratch wound assay. Chromatin remodeling was visualized and quantified during cell migration, which may be intertwined with nuclear mechanics and shape. Inhibition disrupts remodeling and other unknown roles in chromatin, thus affecting the speed and persistence of cell migration. Interestingly, cytoskeletal stress fiber formation and cell shape were not visibly affected by chromatin modifications, suggesting an exclusive nuclear mechanobiological role in cell migration. These findings provide new insights into how aging and other degenerative conditions affect the plasticity of chromatin architecture and hence its effect on cell migration efficiency.
Glucocorticoids suppress NF-κB-mediated neutrophil control ofAspergillus fumigatushyphal growth
Authors: Thrikawala Savini U. , Anderson Molly , Rosowski Emily E. 
Published: December 2023

AbstractGlucocorticoids are a major class of therapeutic anti-inflammatory and immunosuppressive drugs prescribed to patients with inflammatory diseases, to avoid transplant rejection, and as part of cancer chemotherapy. However, exposure to these drugs increases the risk of opportunistic infections such as with the fungusAspergillus fumigatus. Prolonged glucocorticoid therapy is one of the main risks for invasive aspergillosis, which causes mortality in >50% of infected patients. The mechanisms by which glucocorticoids increase susceptibility toA. fumigatusare poorly understood. Here, we used a zebrafish larva-Aspergillusinfection model to identify innate immune mechanisms altered by glucocorticoid treatment. Infected larvae exposed to dexamethasone succumb to the infection at a significantly higher rate than control larvae. However, both macrophages and neutrophils are still recruited to the site of infection and dexamethasone treatment does not significantly affect fungal spore killing. Instead, the primary effect of dexamethasone manifests later in infection with treated larvae exhibiting increased invasive hyphal growth. In line with this, dexamethasone predominantly inhibits neutrophil function, rather than macrophage function. Dexamethasone-induced mortality also depends on the glucocorticoid receptor. One pathway that glucocorticoids can inhibit is NF-κB activation and we report that dexamethasone partially suppresses NF-κB activation at the infection site by inducing the transcription of IκB via the glucocorticoid receptor. Independent CRISPR/Cas9 targeting of IKKγ to prevent NF-κB activation also increases invasiveA. fumigatusgrowth and larval mortality. However, dexamethasone treatment of IKKγ crispant larvae further increases invasive hyphal growth, suggesting that dexamethasone may suppress other pathways in addition to NF-κB to promote host susceptibility. Collectively, we find that dexamethasone acts through the glucocorticoid receptor to suppress NF-κB-mediated neutrophil control ofA. fumigatushyphae in zebrafish larvae.Author SummaryGlucocorticoids are drugs that stop inflammation and suppress the immune system. Glucocorticoids are effective in treating inflammatory diseases such as asthma and arthritis, preventing organ rejection after transplant surgery, and in ameliorating the side effects of cancer chemotherapy. However, as these drugs suppress the immune system, patients taking glucocorticoids are more prone to infections such as with the environmental fungusAspergillus fumigatus. The specific mechanisms that glucocorticoids inhibit to increase susceptibility to infection are largely unknown. Here, we used a larval zebrafish model ofA. fumigatusinfection to determine that glucocorticoids mainly suppress the ability of neutrophils to control the fungal hyphal growth that causes tissue damage. Our study provides insight into future strategies to treatA. fumigatusinfection in patients undergoing glucocorticoid therapy.
Normalization and gene selection for single-cell RNA-seq UMI data using sampling-adjusted sums of squares of Pearson residuals with a Poisson model
Authors: Klebanoff Victor 
Published: December 2023

AbstractSCTransforminSeuratandscanpy.experimental.pp.recipe pearson residuals(scanpyhenceforth) normalize UMI counts as Pearson residuals of negative binomial models. Residual variance scores genes for downstream analysis. Although we observed that both methods usually assign the highest scores to the same genes, for many highly ranked genes (e.g. among the top 2,000) scores may be unstable – not robust to the selection of cells used to calculate residuals. As an alternative, we consider the Poisson model, for which a natural score is the mean sum of squares of Pearson residuals. We show that these scores can be unstable if a gene’s nonzero UMI counts are concentrated on a small number of cells. This explains the instability forscanpybecause of its similarity to the Poisson model. We define a metric for genes’ instability and observe that for all three methods it is negatively correlated with the number of cells on which genes’ counts are nonzero. To reduce the instability of scores based on the Poisson model, we score each gene using multiple random samples of approximately half of the cells. The minimum of these values defines a “sampling-adjusted” score. For data that we analyzed, these are more stable than scores fromSCTransformandscanpywhile generally agreeing with them on the highest ranked genes. As a second criterion to compare our proposal withSCTransform, we use differential expression analysis. For genes with high scores, the residuals’ Kruskal-Wallis H-statistics are generally greater for our method than forSCTransformand are more highly correlated with our method’s scores.
Mechanisms by which barrier-to-autointegration factor regulates dynamics of nucleocytoplasmic leakage and membrane repair following nuclear envelope rupture
Authors: Halfmann Charles T. , Scott Kelsey L. , Sears Rhiannon M. , Roux Kyle J. 
Published: December 2023

AbstractThe nuclear envelope (NE) creates a barrier between the cytosol and nucleus during interphase that is key for cellular compartmentalization and protecting genomic DNA. NE rupture can expose genomic DNA to the cytosol and allow admixture of the nuclear and cytosolic constituents, a proposed mechanism of cancer and NE-associated diseases. Barrier-to-autointegration factor (BAF) is a DNA-binding protein that localizes to NE ruptures where it recruits LEM-domain proteins, A-type lamins, and participates in rupture repair. To further reveal the mechanisms by which BAF responds to and aids in repairing NE ruptures, we investigated known properties of BAF including LEM domain binding, lamin binding, compartmentalization, phosphoregulation of DNA binding, and BAF dimerization. We demonstrate that it is the cytosolic population of BAF that functionally repairs NE ruptures, and phosphoregulation of BAF’s DNA-binding that enables its ability to facilitate that repair. Interestingly, BAF’s LEM or lamin binding activity appears dispensable for its role in functional repair. Furthermore, we demonstrate that BAF functions to reduce the extent of leakage though NE ruptures, suggesting that BAF effectively forms a diffusion barrier prior to NE repair. Collectively, these results enhances our knowledge of the mechanisms by which BAF responds to NE ruptures and facilitates their repair.
Presenilin-dependent regulation of tau pathology via the autophagy/proteasome pathway
Authors: del Ser-Badia Anna , Soto-Faguás Carlos M. , Vecino Rebeca , Rodríguez-Alvarez José , Vicario Carlos , Saura Carlos A. 
Published: December 2023

AbstractAutosomal dominant inherited mutations in the presenilin (PS/PSEN) genes cause early-onset familial Alzheimer’s disease (AD) by enhancing cerebral accumulation of amyloid-β (Aβ) and microtubule-associated protein tau, although the precise cellular mechanisms by which PS dysfunction drives neuronal tau pathology remain still unclear. Here, we investigated the mechanisms linking PS/γ-secretase-dependent tau pathology and autophagy by using molecular, imaging and pathological approaches in brains, fibroblasts and induced pluripotent stem cells (iPSCs)-derived neurons from mutantPSEN1carriers, as well as in a novel tauopathy mouse model lackingPSin glutamatergic neurons. We found colocalization of phosphorylated tau with the autophagy marker p62 in the hippocampus of tauopathy patients withPSEN1mutations, corticobasal degeneration and Pick’s disease. Remarkably, disrupted autophagic clearance of pathological tau was evidenced by increased autophagy markers and accumulation of total and AD-associated phosphorylated tau species (pTau 181, 202, 217) in hippocampal lysates and autophagosomes of familial AD-linkedPSEN1patients andPS-deficient tau transgenic mice. Human iPSC-derived neurons harboring the familial AD-linkedPSEN1G206D mutation are less sensitive to autophagy inhibition, reduce tau release and accumulate intracellular tau oligomers. Human primary fibroblasts fromPSEN1G206D and/or L286P carriers show elevated LC3 and autolysosomes indicating that these familial AD-linkedPSEN1mutations disrupt autophagy flux. PS is required for efficient autophagy-mediated tau degradation in neurons through a dual mechanism involving autophagy induction via blockage of Akt/PRAS40-dependent mTORC1 activation and promoting autophagosome/lysosome fusion. Surprisingly, pharmacological proteasome inhibition decreases tau accumulation in neurons by promoting tau release through a mechanism that requires functionalPS.In conclusion, PS is required for autophagy/proteasome-mediated tau elimination in neurons, while familial AD-linkedPSENmutations cause progressive tau pathology by disrupting autophagy. These findings may impact on the development of new therapeutic targets for tauopathy dementias.
Infection and antibiotic-associated changes in the fecal microbiota ofC. rodentiumϕstx2dact-infected C57BL/6 mice
Authors: Mühlen Sabrina , Heroven Ann Kathrin , Elxnat Bettina , Kahl Silke , Pieper Dietmar H. , Dersch Petra 
Published: December 2023

ABSTRACTEnterohemorrhagicE. colicauses watery to bloody diarrhea, which may progress to hemorrhagic colitis and hemolytic-uremic syndrome. While early studies suggested that antibiotic treatment may worsen the pathology of an EHEC infection, recent work has shown that certain non-Shiga toxin-inducing antibiotics avert disease progression. Unfortunately, both intestinal bacterial infections and antibiotic treatment are associated with dysbiosis. This can alleviate colonization resistance, facilitate secondary infections, and potentially lead to more severe illness. To address the consequences in the context of an EHEC infection, we used the established mouse infection model organismC. rodentiumϕstx2dactand monitored changes in fecal microbiota composition during infection and antibiotic treatment.C. rodentiumϕstx2dactinfection resulted in minor changes compared to antibiotic treatment. The infection caused clear alterations in the microbial community, leading mainly to a reduction of Muribaculaceae and a transient increase in Enterobacteriaceae distinct fromCitrobacter. Antibiotic treatments of the infection resulted in marked and distinct variations in microbiota composition, diversity, and dispersion. Enrofloxacin and trimethoprim/sulfamethoxazole, which did not prevent Stx-mediated organ damage, had the least disruptive effects on the intestinal microbiota, while kanamycin and tetracycline, which rapidly cleared the infection, caused a severe reduction in diversity. Kanamycin treatment resulted in the depletion of all but Bacteroidetes genera, whereas tetracycline effects on Clostridia were less severe. Together, these data highlight the need to address the impact of individual antibiotics in the clinical care of life-threatening infections and consider microbiota-regenerating therapies.IMPORTANCEUnderstanding the impact of antibiotic treatment on enterohemorrhagicE. coli(EHEC) infections is crucial for appropriate clinical care. While discouraged by early studies, recent findings suggest certain antibiotics can impede disease progression. Here, we investigated the impact of individual antibiotics on the fecal microbiota in the context of an established EHEC mouse model usingC. rodentiumϕstx2dact. The infection caused significant variations in the microbiota, leading to a transient increase in Enterobacteriaceae distinct fromCitrobacter. However, these effects were minor compared to those observed for antibiotic treatments. Indeed, antibiotics that most efficiently cleared the infection also had the most detrimental effect on the fecal microbiota, causing a substantial reduction in microbial diversity. Conversely, antibiotics showing adverse effects or incomplete bacterial clearance had a reduced impact on microbiota composition and diversity. Taken together, our findings emphasize the delicate balance required to weigh the harmful effects of infection and antibiosis in treatment.
Benchmarking feature selection and feature extraction methods to improve the performances of machine-learning algorithms for patient classification using metabolomics biomedical data
Authors: Labory Justine , Njomgue-Fotso Evariste , Bottini Silvia 
Published: December 2023

AbstractObjectiveClassification tasks are an open challenge in the field of biomedicine. While several machine-learning techniques exist to accomplish this objective, several peculiarities associated with biomedical data, especially when it comes to omics measurements, prevent their use or good performance achievements. Omics approaches aim to understand a complex biological system through systematic analysis of its content at the molecular level. On the other hand, omics data are heterogeneous, sparse and affected by the classical “curse of dimensionality” problem, i.e. having much fewer observation samples (n) than omics features (p). Furthermore, a major problem with multi- omics data is the imbalance either at the class or feature level. The objective of this work is to study whether feature extraction and/or feature selection techniques can improve the performances of classification machine-learning algorithms on omics measurements.MethodsAmong all omics, metabolomics has emerged as a powerful tool in cancer research, facilitating a deeper understanding of the complex metabolic landscape associated with tumorigenesis and tumor progression. Thus, we selected three publicly available metabolomics datasets, and we applied several feature extraction techniques both linear and non-linear, coupled or not with feature selection methods, and evaluated the performances regarding patient classification in the different configurations for the three datasets.ResultsWe provide general workflow and guidelines on when to use those techniques depending on the characteristics of the data available. For the three datasets, we showed that applying feature selection based on biological previous knowledge improves the performances of the classifiers. Notebook used to perform all analysis are available at:https://github.com/Plant-Net/Metabolomic_project/.
Deletion of Glyoxalase 1 exacerbates acetaminophen-induced hepatotoxicity in mice
Authors: Dobariya Prakashkumar , Xie Wei , Rao Swetha Pavani , Xie Jiashu , Seelig Davis M. , Vince Robert , Lee Michael K. , More Swati S. 
Published: December 2023

ABSTRACTAcetaminophen (APAP) overdose triggers a cascade of intracellular oxidative stress events culminating in acute liver injury. The clinically used antidote, N-acetylcysteine (NAC) has a narrow therapeutic window and early treatment is essential for satisfactory therapeutic outcome. For more versatile therapies that can be effective even at late-presentation, the intricacies of APAP-induced hepatotoxicity must be better understood. Accumulation of advanced glycation end-products (AGEs) and consequent activation of the receptor for AGEs (RAGE) are considered one of the key mechanistic features of APAP toxicity. Glyoxalase-1 (Glo-1) regulates AGE formation by limiting the levels of methylglyoxal (MEG). In this study, we studied the relevance of Glo-1 in APAP mediated activation of RAGE and downstream cell-death cascades. Constitutive Glo-1 knockout mice (GKO) and a cofactor of Glo-1, ψ-GSH, were employed as tools. Our findings show elevated oxidative stress, activation of RAGE and hepatocyte necrosis through steatosis in GKO mice treated with high-dose APAP compared to wild type controls. A unique feature of the hepatic necrosis in GKO mice is the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than inflammation seen in wild type. The GSH surrogate and general antioxidant, ψ-GSH alleviated APAP toxicity irrespective of Glo-1 status, suggesting that oxidative stress being the primary driver of APAP toxicity. Overall, exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against initial stages of APAP overdose.
Alternate routes to mnm5s2U synthesis in Gram-positive bacteria
Authors: Jaroch Marshall , Sun Guangxin , Tsui Ho-Ching Tiffany , Reed Colbie , Sun Jinjing , Jörg Marko , Winkler Malcolm E. , Rice Kelly C. , Stich Troy A. , Dedon Peter C. , Dos Santos Patricia C. , de Crécy-Lagard Valérie 
Published: December 2023

AbstractThe wobble bases of tRNAs that decode split codons are often heavily modified. In Bacteria tRNAGlu,Gln,Aspcontain a variety of xnm5s2U derivatives. The synthesis pathway for these modifications is complex and fully elucidated only in a handful of organisms, including the Gram-negativeEscherichia coliK12 model. Despite the ubiquitous presence of mnm5s2U modification, genomic analysis shows the absence ofmnmCorthologous genes, suggesting the occurrence of alternate biosynthetic schemes for the installation of this modification. Using a combination of comparative genomics and genetic studies, a member of the YtqA subgroup of the Radical Sam superfamily was found to be involved in the synthesis of mnm5s2U in bothBacillus subtilisandStreptococcus mutans. This protein, renamed MnmL, is encoded in an operon with the recently discovered MnmM methylase involved in the methylation of the pathway intermediate nm5s2U into mnm5s2U inB. subtilis. Analysis of tRNA modifications of bothS. mutansandStreptococcus pneumoniaeshows that growth conditions and genetic backgrounds influence the ratios of pathways intermediates in regulatory loops that are not yet understood. The MnmLM pathway is widespread along the bacterial tree, with some phyla, such as Bacilli, relying exclusively on these two enzymes. The occurrence of fusion proteins, alternate arrangements of biosynthetic components, and loss of biosynthetic branches provide examples of biosynthetic diversity to retain a conserved tRNA modification in nature.ImportanceThe xnm5s2U modifications found in several tRNAs at the wobble base position are widespread in Bacteria where they have an important role in decoding efficiency and accuracy. This work identifies a novel enzyme (MnmL) that is a member of a subgroup of the very versatile Radical SAM superfamily and is involved in the synthesis of mnm5s2U in several Gram-positive bacteria, including human pathogens. This is another novel example of a non-orthologous displacement in the field of tRNA modification synthesis, showing how different solutions evolve to retain U34 tRNA modifications.
Spatial analysis of NOS2 and COX2 interaction with T-effector cells reveals immunosuppressive landscapes associated with poor outcome in ER- breast cancer patients
Authors: Ridnour Lisa A. , Cheng Robert Y.S. , Heinz William F. , Pore Milind , Gonzalez Ana L. , Femino Elise L. , Moffat Rebecca , Wink Adelaide L. , Imtiaz Fatima , Coutinho Leandro , Butcher Donna , Edmondson Elijah F. , Rangel M. Cristina , Wong Stephen T.C. , Lipkowitz Stanley , Glynn Sharon , Vitek Michael P. , McVicar Daniel W. , Li Xiaoxian , Anderson Stephen K. , Paolocci Nazareno , Hewitt Stephen M. , Ambs Stefan , Billiar Timothy R. , Chang Jenny C. , Lockett Stephen J. , Wink David A. 
Published: December 2023

AbstractMultiple immunosuppressive mechanisms exist in the tumor microenvironment that drive poor outcomes and decrease treatment efficacy. The co-expression of NOS2 and COX2 is a strong predictor of poor prognosis in ER- breast cancer and other malignancies. Together, they generate pro-oncogenic signals that drive metastasis, drug resistance, cancer stemness, and immune suppression. Using an ER- breast cancer patient cohort, we found that the spatial expression patterns of NOS2 and COX2 with CD3+CD8+PD1- T effector (Teff) cells formed a tumor immune landscape that correlated with poor outcome. NOS2 was primarily associated with the tumor-immune interface, whereas COX2 was associated with immune desert regions of the tumor lacking Teff cells. A higher ratio of NOS2 or COX2 to Teff was highly correlated with poor outcomes. Spatial analysis revealed that regional clustering of NOS2 and COX2 was associated with stromal-restricted Teff, while only COX2 was predominant in immune deserts. Examination of other immunosuppressive elements, such as PDL1/PD1, Treg, B7H4, and IDO1, revealed that PDL1/PD1, Treg, and IDO1 were primarily associated with restricted Teff, whereas B7H4 and COX2 were found in tumor immune deserts. Regardless of the survival outcome, other leukocytes, such as CD4 T cells and macrophages, were primarily in stromal lymphoid aggregates. Finally, in a 4T1 model, COX2 inhibition led to a massive cell infiltration, thus validating the hypothesis that COX2 is an essential component of the Teff exclusion process and, thus, tumor evasion. Our study indicates that NOS2/COX2 expression plays a central role in tumor immunosuppression. Our findings indicate that new strategies combining clinically available NOS2/COX2 inhibitors with various forms of immune therapy may open a new avenue for the treatment of aggressive ER- breast cancers.