bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemical exploration of a highly selective scaffold with activity against intracellular Mycobacterium tuberculosis
Authors: Njikan Samuel , Ahmed Sara , Manning Alyssa , Awasthi Divya , Ovechkina Yulia , Chowdhury Sultan , Butts Arielle , Parish Tanya 
Published: February 2022

AbstractWe previously identified a phenylthiourea series with activity against intracellular Mycobacterium tuberculosis using a high throughput, high content assay. We conducted a catalog structure-activity relationship study with a collection of 35 analogs. We identified several thiourea derivatives with excellent potency against intracellular bacteria and good selectivity over eukaryotic cells. Compounds had much lower activity against extracellular bacteria which was not increased by using cholesterol as the sole carbon source. Compounds were equally active against strains with mutations in QcrB or MmpL3, thereby excluding common, promiscuous targets as the mode of action. The phenylthiourea series represents a good starting point for further exploration to develop novel anti-tubercular agents.
Ovarian carcinosarcoma is a distinct form of ovarian cancer with poorer survival compared to tubo-ovarian high grade serous carcinoma
Authors: Hollis Robert L. , Croy Ian , Churchman Mike , Bartos Clare , Rye Tzyvia , Gourley Charlie , Herrington C. Simon 
Published: February 2022

ABSTRACTBACKGROUNDOvarian carcinosarcoma (OCS) is an uncommon, biphasic and highly aggressive ovarian cancer type, which has received relatively little research attention.METHODSWe curated the largest pathologically-confirmed OCS cohort to date, performing detailed histopathological characterisation, analysis of features associated with survival, and comparison against high grade serous ovarian carcinoma (HGSOC).RESULTS82 OCS patients were identified; overall survival was poor (median 12.7 months). 79% demonstrated epithelial components of high grade serous (HGS) type, while 21% were endometrioid. Heterologous elements were common (chondrosarcoma in 32%, rhabdomyosarcoma in 21%, liposarcoma in 2%); chondrosarcoma was more frequent in OCS with carcinomatous components of endometrioid type. Earlier stage, complete surgical resection, and treatment with platinum-containing chemotherapy were associated with prolonged survival; however, risk of relapse and mortality was high across all patient groups. Histological subclassification did not identify subgroups with distinct survival. Compared to HGSOC, OCS patients were older at diagnosis (P<0.0001), more likely to be FIGO stage I (P=0.025), demonstrated lower chemotherapy response rate (P=0.001) and had significantly poorer survival (P<0.0001).CONCLUSIONOCS represents a distinct, highly lethal form of ovarian cancer for which new treatment strategies are urgently needed. Aggressive adjuvant chemotherapy should be considered for all patients, including those with early stage disease.
Risk of SARS-CoV-2 reinfection 18 months after primary infection: population-level observational study
Authors: Flacco Maria Elena , Soldato Graziella , Martellucci Cecilia Acuti , Di Martino Giuseppe , Carota Roberto , Caponetti Antonio , Manzoli Lamberto 
Published: February 2022

AbstractCurrent data suggest that SARS-CoV-2 reinfections are rare, but uncertainties remain on the duration of the natural immunity, its protection against Omicron variant, finally the impact of vaccination to reduce reinfection rates. In this retrospective cohort analysis of the entire population of an Italian Region, we followed 1,293,941 subjects from the beginning of the pandemic to the current scenario of Omicron predominance (up to mid-January 2022). After an average of 334 days, we recorded 260 reinfections among 84,907 previously infected subjects (overall rate: 0.31%), two hospitalizations (2.4 x100,000), and one death. Importantly, the incidence of reinfection did not vary substantially over time: after 18-22 months from the primary infection, the reinfection rate was still 0.32%, suggesting that protection conferred by natural immunity may last beyond 12 months. The risk of reinfection was significantly higher among the unvaccinated subjects, and during the Omicron wave.
A Chromodomain Mutation Identifies Separable Roles for C. elegans MRG-1 in Germline and Somatic Development
Authors: Doronio Christine A. , Ling Huiping , Gleason Elizabeth J. , Kelly William G. 
Published: February 2022

ABSTRACTThe packaging of DNA into chromatin strongly influences gene regulation. Post-translational modifications of histones, and the proteins that bind to them, alter the accessibility of chromatin and contribute to the activation and repression of genes. The human MRG15 (MORF4- Related Gene on chromosome 15) protein is a conserved chromodomain-containing protein that binds to methylated lysine 36 on histone H3 (H3K36me) and plays important roles in development, genome integrity, and gene regulation. MRG15 affects transcriptional regulation through its interactions with both histone acetyltransferase (HAT) and histone deacetylase (HDAC) complexes. MRG-1, its C. elegans homolog, has similarly been shown to have important roles in genomic integrity and development, and has also been shown to co- purify with HDAC complexes. Like MRG15, MRG-1 is predicted to bind to H3K36me through its chromodomain, yet despite mrg-1 mutants displaying developmental and germline phenotypes that overlap with H3K36 methyltransferase mutants, the role of the MRG-1 chromodomain has never been characterized. In this study, we examined meiotic cells lacking H3K36me3 to compare to mrg-1 mutant germ cell phenotypes, and mutated key residues in the MRG-1 chromodomain (CD) to assess its function. The CD mutations cause embryonic lethality but few post-embryonic germline defects, in contrast to mrg-1 deletion mutants which are viable but sterile. The CD mutations therefore disrupt somatic development despite the apparent absence of a requirement for MRG-1 protein in embryogenesis. Furthermore, the CD mutants exhibit a dominant RNAi resistance phenotype that is not seen in other mrg-1 mutant alleles. This suggests that the function of MRG-1, and the chromatin modifying complexes with which it interacts, includes tissue-specific interactions involving different requirements for a functional chromodomain. We propose that the CD mutation disrupts proper guidance of complexes within which it acts, and this guidance defect results in improper HDAC and/or HAT regulation causing an indirect defect in RNAi machinery expression or targeting.
Protein profiling of WERI RB1 and etoposide resistant WERI ETOR reveals new insights into topoisomerase inhibitor resistance in retinoblastoma
Authors: Kakkassery Vinodh , Gemoll Timo , Krämer Miriam M. , Sauer Thorben , Tura Aysegül , Ranjbar Mahdy , Grisanti Salvatore , Joachim Stephanie C. , Mergler Stefan , Reinhard Jacqueline 
Published: February 2022

AbstractChemotherapy resistance is one of the reasons for eye loss in patients with retinoblastoma (RB). RB chemotherapy resistance has been studied in different cell culture models such as WERI RB1. In addition, chemotherapy resistant RB subclones like the etoposide resistant WERI ETOR cell line have been established to improve the understanding of chemotherapy resistance in RB. The objective of this study was to characterize cell line models of an etoposide sensitive WERI RB1 and its etoposide resistant subclone WERI ETOR by proteomic analysis. Subsequently, quantitative proteomic data served for correlation analysis with known drug perturbation profiles. Methodically, WERI RB1 and WERI ETOR were cultured and prepared for quantitative mass spectrometry (MS). This was carried out in a data-independent acquisition (DIA) mode (Sequential Window Acquisition of All Theoretical Mass Spectra, SWATH-MS). The raw SWATH files were processed using neural networks in a library free mode along with machine learning algorithms. Pathway enrichment was performed using the REACTOME pathway resource and correlated to the Molecular Signature Database (MSigDB) hallmark gene set collections for functional annotation. Furthermore, a drug connectivity analysis using the L1000 database was used to correlate the mechanism-of-action (MOA) for different anticancer reagents to WERI RB1/WERI ETOR signatures. A total of 4,756 proteins were identified across all samples, showing a distinct clustering between the groups. Of these proteins, 64 were significantly altered (q < 0.05 & log2FC |>2|, 22% higher in WERI ETOR). Pathway analysis revealed an enriched metabolic pathway for “retinoid metabolism and transport” in WERI ETOR and for “sphingolipid de novo biosynthesis” in WERI RB1. In addition, this study revealed similar protein signatures of topoisomerase inhibitors in WERI ETOR as well as ATPase inhibitors, acetylcholine receptor antagonists and vascular endothelial growth factor receptor (VEGFR) inhibitors in WERI RB1. In this study, WERI RB1 and WERI ETOR were analyzed as a cell line model for chemotherapy resistance in RB using data-independent MS. The global proteome identified activation of “sphingolipid de novo biosynthesis” in WERI RB1 and revealed future potential treatment options for etoposide resistance in RB.
Tyrosine kinase inhibitors trigger lysosomal damage-associated cell lysis to activate the NLRP3 inflammasome
Authors: Neuwirt Emilia , Magnani Giovanni , Ćiković Tamara , Kostina Anna , Wöhrle Svenja , Flemming Stephan , Fischer Larissa , Fischenich Nora J. , Saller Benedikt S. , Gorka Oliver , Renner Steffen , Agarinis Claudia , Parker Christian , Boettcher Andreas , Farady Christopher J. , Backofen Rolf , Rodriguez-Franco Marta , Tholen Martina , Reinheckel Thomas , Ott Thomas , Groß Christina J. , Jost Philipp J. , Groß Olaf 
Published: February 2022

AbstractInflammasomes are intracellular protein complexes that control proteolytic maturation and secretion of inflammatory interleukin-1 (IL-1) family cytokines and are thus important in host defense. While some inflammasomes are activated simply by binding to pathogen-derived molecules, others, including those nucleated by NLRP3 and NLRP1, have more complex activation mechanisms that are not fully understood. We screened a library of small molecules to identify new inflammasome activators that might shed light on activation mechanisms. In addition to validating dipeptidyl peptidase (DPP) inhibitors as NLRP1 activators, we find that clinical tyrosine kinase inhibitors (TKIs) including imatinib and masitinib activate the NLRP3 inflammasome. Mechanistically, these TKIs cause lysosomal swelling and damage, leading to cathepsin-mediated destabilization of myeloid cell membranes and cell lysis. This is accompanied by potassium (K+) efflux, which activates NLRP3. Both lytic cell death and NLRP3 activation but not lysosomal damage induced by TKIs are prevented by the cytoprotectant high molecular weight polyethylene glycol (PEG). Our study establishes a screening method that can be expanded for inflammasome research and immunostimulatory drug development, and provides new insight into immunological off-targets that may contribute to efficacy or adverse effects of TKIs.One Sentence SummaryA functional small molecule screen identifies imatinib, masitinib and other tyrosine kinase inhibitors that destabilize myeloid cell lysosomes, leading to cell lysis and K+ efflux-dependent NLRP3 inflammasome activation.
Towards phage therapy for acne vulgaris: Topical application in a mouse model
Authors: Rimon Amit , Rakov Chani , Lerer Vanda , Sheffer-Levi Sivan , Alkalky-Oren Sivan , Shlomov Tehila , Shasha Lihi , Lubin Ruthi , Coppenhagen-Glazer Shunit , Molho-Pessach Vered , Hazan Ronen 
Published: February 2022

SUMMARYAcne vulgaris is a common neutrophile-driven inflammatory skin disorder in whichCutibacterium acnes(C. acnes) bacteria play a significant role. Until now, antibiotics have been widely used to treat acne vulgaris, with the inevitable increase in bacterial antibiotic resistance. Phage therapy is a promising solution to the rising problem of antibiotic-resistant bacteria, utilizing viruses that specifically lyse bacteria.Here, we explored the feasibility of phage therapy againstC. acnes. By combining eight novel phages we had isolated, together with commonly used antibiotics, we achieved 100% eradication of clinically isolatedC. acnesstrains. Using topical phage therapy in an acne mouse model resulted in significantly superior clinical scores, as well as a reduction in neutrophil infiltration compared to the control group. These results demonstrate the potential of phage therapy in acne vulgaris treatment, especially when antibiotic-resistant strains are involved.
Interplay between external inputs and recurrent dynamics during movement preparation and execution in a network model of motor cortex
Authors: Bachschmid-Romano Ludovica , Hatsopoulos Nicholas G. , Brunel Nicolas 
Published: February 2022

AbstractThe primary motor cortex has been shown to coordinate movement preparation and execution through computations in approximately orthogonal subspaces. The underlying network mechanisms, and the roles played by external and recurrent connectivity, are central open questions that need to be answered to understand the neural substrates of motor control. We develop a recurrent neural network model that recapitulates the temporal evolution of neuronal activity recorded from the primary motor cortex of a macaque monkey during an instructed delayed-reach task. In particular, it reproduces the observed dynamic patterns of covariation between neural activity and the direction of motion. We explore the hypothesis that the observed dynamics emerges from a synaptic connectivity structure that depends on the preferred directions of neurons in both preparatory and movement-related epochs, and we constrain the strength of both synaptic connectivity and external input parameters from data. While the model can reproduce neural activity for multiple combinations of the feedforward and recurrent connections, the solution that requires minimum external inputs is one where the observed patterns of covariance are shaped by external inputs during movement preparation, while they are dominated by strong direction-specific recurrent connectivity during movement execution, in agreement with recent experimental findings on the relationship between motor–cortical and motor–thalamic activity, both before and during movement execution. Our model also demonstrates that the way in which single-neuron tuning properties change over time can explain the level of orthogonality of preparatory and movement-related subspaces.
Improved pathogen and stress tolerance in tomato mutants of SET domain histone 3 lysine methyltransferases
Authors: Bvindi Carol , Lee Sanghun , Tang Liang , Mickelbart Michael V. , Li Ying , Mengiste Tesfaye 
Published: February 2022

AbstractHistone lysine methylations (HLMs) are implicated in control of gene expression in different eukaryotes. However, the role of HLMs in regulating desirable crop traits and the enzymes involved in these modifications are poorly understood. We studied the functions of tomato histone H3 lysine methyltransferases Set Domain Group 33 (SDG33) and SDG34 in biotic and abiotic stress responses. SDG33 and SDG34 mutants were altered in H3K36 and H3K4 methylations, and expression of genes involved in diverse processes and responses to biotic and abiotic stimuli. The double but not the single mutants show resistance to the fungal pathogen Botrytis cinerea. Interestingly, single mutants were tolerant to drought and the double mutant showed superior tolerance consistent with independent and additive functions. Mutants maintained higher water status during drought and improved recovery and survival after lapse of drought. Notably, diminution of H3K4 and H3K36 trimethylation and expression of negative regulators in challenged plants contributes to stress tolerance of the mutants. Mutations in SDG33 and SDG34 remove predisposition to biotic and abiotic stress by disrupting permissive transcriptional context promoting expression of negative regulatory factors. These allows improvement of stress and pathogen tolerance through modification of histone epigenetic marks.
Accurate proteome-wide measurement of methionine oxidation in aging mouse brains
Authors: Bettinger John Q. , Simon Matthew , Korotkov Anatoly , Welle Kevin A. , Hryhorenko Jennifer R. , Seluanov Andrei , Gorbunova Vera , Ghaemmaghami Sina 
Published: February 2022

AbstractThe oxidation of methionine side chains has emerged as an important posttranslational modification of proteins. A diverse array of low-throughput and targeted studies have suggested that the oxidation of methionine residues in select proteins can have diverse impacts on cell physiology, ranging from detrimental effects on protein structure and stability to functional roles in cell signaling. Despite its importance, the large-scale investigation of methionine oxidation in a complex matrix, such as the cellular proteome, has been historically hampered by technical limitations. Herein we report a methodology, Methionine Oxidation by Blocking (MobB), that allows for accurate and precise quantification of low levels of methionine oxidation typically observed in vivo. To demonstrate the utility of this methodology, we applied MobB to the brain tissues of young (6 m.o.) and old (20 m.o.) mice and identified over 280 novel sites for in vivo methionine oxidation. We further demonstrated that oxidation stoichiometries for specific methionine residues are highly consistent between individual animals and methionine sulfoxides are enriched in clusters of functionally related gene products including membrane and extracellular proteins. However, we did not detect significant changes in methionine oxidation in brains of old mice. Our results suggest that under normal in vivo conditions methionine oxidation is a biologically regulated process rather than a result of stochastic chemical damage.
Resistance to EGFR inhibitors in lung cancer occurs through horizontal transfer and is associated with increased caveolins expression
Authors: Junqueira-Neto Susana , Oliveira Ana R. , Marques Joana F. , Oliveira Patrícia , Fernandes Maria G. , Hespanhol Venceslau , Barroso Ana , Pinheiro Jorge , Souto-Moura Conceição , Cavadas Bruno , Pereira Luísa , Adem Bárbara , Silva Miguel , Melo Sónia A. , Costa José L. , Machado José C. 
Published: February 2022

AbstractResistance to treatment is a major clinical problem and a major cause of cancer-related deaths. Understanding the biological basis of resistance acquisition is of utmost importance to improve the clinical management of cancer patients. NGS analysis of human lung cancer (LC) tumors from patients that relapsed after treatment with EGFR-tyrosine kinase inhibitors (TKI), revealed that the p.T790M resistance mutation is not present in all the relapsing tumor cells, suggesting that LC cells can become resistant even if not carrying the p.T790M mutation. Using in vitro treatments with conditioned medium (CM) and in vivo co-inoculation experiments, we show that LC cells sensitive to EGFR-TKIs (S cells) acquire resistance faster when treated with CM from LC cells resistant to EGFR-TKIs (R cells) or when co-inoculated with R cells in opposite flanks of the same animal. Importantly, we show that acquisition of resistance is not due to the emergence of subpopulations of cancer cells with new resistance mutations. Using transcriptomics, we show that acquisition of resistance is associated with upregulation of genes involved in endocytosis, namely caveolins CAV1 and CAV2. These findings were validated in human clinical samples, where an increase in CAV1 and CAV2 expression was associated with tumor relapse after treatment with EGFR-TKIs. Our results suggest that acquisition of resistance to targeted therapies results from the combined effect of selection of cells harboring specific resistance mutations and horizontal transfer of the resistance phenotype. These findings may pave the way to bring intercellular communication into the realm of cancer treatment.One Sentence SummaryResistance to EGFR inhibitors is transferred horizontally between lung cancer cells and is associated with gain of expression of caveolins.
The effects of brief heat during early booting on reproductive, developmental and physiological performance in common wheat (Triticum aestivum L.)
Authors: Xu Jiemeng , Lowe Claudia , Hernandez-Leon Sergio G. , Dreisigacker Susanne , Reynolds Matthew P. , Valenzuela-Soto Elisa M. , Paul Matthew J. , Heuer Sigrid 
Published: February 2022

ABSTRACTRising temperatures due to climate change threaten agricultural crop productivity. As a cool-season crop wheat is heat sensitive, but often exposed to high temperatures during cultivation. In the current study, a bread wheat panel of spring wheat genotypes, including putatively heat-tolerant Australian and CIMMYT genotypes, was exposed to a 5-day mild (34°C/28°C, day/night) or extreme (37°C/27°C) heat stress during the sensitive pollen developmental stage. Worsening effects on anther morphology were observed as heat stress increased from mild to extreme. Even under mild heat a significant decrease in pollen viability and grain number per spike from primary spike was observed compared with the control (21°C/15°C), with Sunstar and two CIMMYT breeding lines performing well. A heat-specific positive correlation between the two traits indicates the important role of pollen fertility for grain setting. Interestingly, both mild and extreme heat induced development of new tillers after the heat stress, providing an alternative sink for accumulated photosynthates and significantly contributing to the final yield. Measurements of flag leaf maximum potential quantum efficiency of Photosystem II (Fv/Fm) showed an initial inhibition after the heat treatment, followed by a full recovery within a few days. Despite this, model fitting using chlorophyll SPAD measurements showed an earlier onset or faster senescence rate under heat stress. The data presented here provide interesting entry points for further research into pollen fertility, tillering dynamics and leaf senescence under heat. The identified tolerant wheat genotypes can be used to dissect the underlying mechanisms and breed climate-resilient wheat.
Molecular Insights into the Recognition of Acetylated Histone Modifications by the BRPF2 Bromodomain
Authors: Barman Soumen , Roy Anirban , Padhan Jyotirmayee , Sudhamalla Babu 
Published: February 2022

ABSTRACTHBO1 (HAT bound to ORC), a member of the MYST family of histone acetyltransferases (HATs), was initially identified as a binding partner of the origin recognition complex (ORC) that acetylates free histone H3, H4, and nucleosomal H3. It functions as a quaternary complex with the BRPF (BRPF1/2/3) scaffolding protein and two accessory proteins, ING4/5 and Eaf6. BRPF2 interaction with HBO1 has been shown to be important for regulating H3K14 acetylation during embryonic development. However, how the BRPF2 directs the HBO1 HAT complex to chromatin to regulate its HAT activity towards nucleosomal substrates remains unclear. Our findings reveal novel interacting partners of the BRPF2 bromodomain that recognizes different acetyllysine residues on the N-terminus of histone H4, H3, and H2A and preferentially binds to H4K5ac, H4K8ac, and H4K5acK12ac modifications. Further, mutational analysis of BRPF2 bromodomain coupled with ITC binding and pull-down assays on the histone substrates identified critical residues responsible for acetyllysine binding. Moreover, the BRPF2 bromodomain could enrich H4K5ac mark-bearing mononucleosomes compared to other acetylated H4 marks. Consistent with this, ChIP-seq analysis revealed that BRPF2 strongly co-localizes with HBO1 at histone H4K5ac and H4K8ac marks near the TSS in the genome. Together, our study provides novel insights into how the histone binding function of the BRPF2 bromodomain directs the recruitment of the HBO1 HAT complex to chromatin to regulate gene expression.