bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolomics and Microbiomics Insights into the Differential Surface Fouling of Brown Algae
Authors: Oppong-Danquah Ernest , Blümel Martina , Tasdemir Deniz 
Published: July 2023

AbstractMarine macroalgae (seaweeds) are key components of marine ecosystems with vital roles in costal habitats. As they release dissolved organic matter and other molecules, seaweeds are under strong settlement pressure by micro- and macro-epibionts. Uncontrolled epibiosis causes surface fouling with detrimental effects on the health and well-being of the organism. Seaweeds control surface epibionts directly by releasing antifouling and antimicrobial metabolites onto their surfaces, and indirectly by recruiting beneficial microorganisms that produce antimicrobial/antifouling metabolites. Three species of the brown algal genusFucus, F. vesiculosus(FV), F. serratus(FS) andF. distichussubsp.evanescens(FE) form theFucusbelt habitat in the Kiel Fjord, Germany. They often co-occur in the same spot but their blades are fouled differently; we observed FE to be the least fouled, and FV to be the most fouled species. This study was designed to investigate the potential factors underlying different fouling intensities on the surfaces of the three co-occurringFucusspp. Their surface metabolomes were analysed by comparative untargeted UPLC-MS/MS based metabolomics to identify marker metabolites influencing the surface fouling. The epiphytic microbial communities of theFucusspp. were also comparatively characterized by high-throughput amplicon sequencing to identify the differences in the surface microbiome of the algae. By employing these omics methods, integrated with multivariate analyses, we identified discriminant metabolites and microbial taxa associated with FE surface, including antimicrobial polar lipids, the fungal generaMucor,Alternaria, and bacterial genusYoonia-Loktanella. These taxa have been previously reported to produce antimicrobial and antifouling compounds, suggesting their potential involvement in the fouling resistance (least fouled) observed on the FE surface relative to the co-occurring algae FS and FV. These findings shed light on the surface metabolome and microbiome ofFucusspp. and their influence in different fouling intensities and also have implications for the conservation of coastal habitats.
Increased beta2-adrenergic signaling is a targetable stimulus essential for bone healing by promoting callus neovascularization
Authors: Jahn Denise , Knapstein Paul Richard , Otto Ellen , Köhli Paul , Sevecke Jan , Graef Frank , Graffmann Christine , Fuchs Melanie , Jiang Shan , Rickert Mayla , Erdmann Cordula , Appelt Jessika , Revend Lawik , Küttner Quin , Witte Jason , Rahmani Adibeh , Duda Georg , Xie Weixin , Donat Antonia , Schinke Thorsten , Ivanov Andranik , Tchouto Mireille Ngokingha , Beule Dieter , Frosch Karl-Heinz , Baranowsky Anke , Tsitsilonis Serafeim , Keller Johannes 
Published: July 2023

AbstractTraumatic brain injury (TBI) is associated with a hyperadrenergic state and paradoxically causes systemic bone loss while accelerating fracture healing. Here, we identify the beta2-adrenergic receptor (Adrb2) as a central mediator of these skeletal manifestations. While the negative effects of TBI on the unfractured skeleton can be explained by the established impact of Adrb2 signaling on bone formation, Adrb2 promotes neovascularization of the fracture callus under conditions of high sympathetic tone, including TBI and advanced age. Mechanistically, norepinephrine stimulates the expression of Vegfa and Cgrp primarily in periosteal cells via Adrb2, both of which synergistically promote the formation of osteogenic type-H vessels in the fracture callus. Accordingly, the beneficial effect of TBI on bone repair is abolished in mice lacking Adrb2 or Cgrp, and aged Adrb2-deficient mice without TBI develop fracture nonunions despite high bone formation in uninjured bone. Pharmacologically, the Adrb2 antagonist propranolol impairs, and the agonist formoterol promotes fracture healing in aged mice by regulating callus neovascularization. Clinically, intravenous beta-adrenergic sympathomimetics are associated with improved callus formation in trauma patients with long bone fractures. Thus, Adrb2 is a novel target for promoting bone healing, and widely used beta-blockers may cause fracture nonunion under conditions of increased sympathetic tone.Abstract FigureArtwork was created in BioRender.
shRNA drop-out screen identifies BRD4 targeting transcription from RNA polymerase II system to activate β-catenin to promote soft-tissue tumor proliferations
Authors: Sun Sylvia Y. , Tsiperson Vlad 
Published: July 2023

AbstractBRD4 (Bromodomain containing protein 4) is a chromatin reader binds to acetylated lysine residues on histones interacting with RNA Pol II, p-TFeb. PDGF-BB was presented here, in soft-tissue tumor, as an oncogenic factor driving cell proliferation, and aberrant BRD4 knockdown significantly reduced tumor aggressiveness and unfavorable prognosis in soft-tissue tumors. To identify suppressive key drivers impeding demoid tumor growth, shRNA drop-out screen analysis identified signature of “transcription from RNA polymerase II promoter” including DDX, Stat3, SMARCA, ATM, SIRT1, cMyc that were recruited with BRD4 interation in activating β-catenin, which is a major key driver mutated in soft-tissue tumor, and its depletion ceased soft-tissue tumor cell growth. Sepcifically, BRD4 mediated PDGF-BB signaling in GSK stimulation through transcriptional regulation from RNA polymerase II activity with PI3K as target, and thus not only canonical β -catenin/TCF4 signaling, but also non-canonical β -catenin conjunction complex response was activated by BRD4 in nucleus involved in promoting cell proliferation. Our study delineated a signaling axis that may allow soft-tissue tumor cells to escape apoptosis during colonization by activating PDGFBB-BRD4-GSK-β -catenin and non-canonical-β-catenin pathway through BRD4 in cancer cells. An efficient treatment for soft-tissue tumors could be accomplished by targeting PDGF and BRD4 survival pathways on soft-tissue tumor cells.
Unveiling the role of SRY in male-biased cancers: Insights into the molecular basis of sex disparities in high-grade glioma and melanoma
Authors: Guardia Gabriela D A , Batista Rafael Loch , Penalva Luiz O. , Galante Pedro A F 
Published: July 2023

ABSTRACTSex disparities have been observed in many tumor types affecting non-reproductive organs. Typically, the incidence and mortality rates of such cancers are higher in men. Although differences in lifestyle and environmental exposures are known contributors, knowledge of the molecular mechanisms driving sexual dimorphism in tumor development and therapy response remains limited. To address this question, we comprehensively studied the sex-determining region Y (SRY) gene, a male-specific gene that is critical in development. First, we screened 2,448 samples from 11 cancer types to identify those with a higher incidence in men and increased expression of SRY. In cases of high-grade glioma and melanoma, men with tumors exhibiting high SRY expression had a worse prognosis. Our results suggest that SRY target genes show altered expression when SRY is overexpressed. These gene sets are linked to cell growth, epithelial-mesenchymal transition, inflammation, and repression of tumor suppressor pathways. In summary, we present the first comprehensive investigation of SRY expression and its association with clinical outcomes in men with high-grade glioma and melanoma. Our results shed light on the molecular basis for sex disparities and lay the foundation for investigation of various target genes and novel cancer treatments in men with high-grade glioma and melanoma.
Reduction of ribosomal expansion segments in yeast species of theMagnusiomyces/Saprochaeteclade
Authors: Brázdovič Filip , Brejová Broňa , Siváková Barbara , Baráth Peter , Vinař Tomáš , Tomáška Ľubomír , Nosek Jozef 
Published: July 2023

AbstractRibosomes are ribonucleoprotein complexes highly conserved across all domains of life. The size differences of ribosomal RNAs (rRNAs) can be mainly attributed to variable regions termed expansion segments (ESs) protruding out from the ribosomal surface. The ESs were found to be involved in a range of processes including ribosome biogenesis and maturation, translation, and co-translational protein modification. Here, we analyze the rRNAs of the yeasts from theMagnusiomyces/Saprochaeteclade belonging to the basal lineages of the subphylum Saccharomycotina. We find that these yeasts are missing more than 400 nt from the 25S rRNA and 150 nt from the 18S rRNAs when compared to their canonical counterparts inSaccharomyces cerevisiae. The missing regions mostly map to ESs, thus representing a shift toward a minimal rRNA structure. Despite the structural changes in rRNAs, we did not identify dramatic alterations of the ribosomal protein inventories. We also show that the size-reduced rRNAs are not limited to the species of theMagnusiomyces/Saprochaeteclade, indicating that the shortening of ESs happened independently in several other lineages of the subphylum Saccharomycotina.SignificanceExpansion segments are variable regions present in the ribosomal RNAs involved in the ribosome biogenesis and translation. Although some of them were shown to be essential, their functions and the evolutionary trajectories leading to their expansion and/or reduction are not fully understood. Here, we show that the yeasts from theMagnusiomyces/Saprochaeteclade have truncated expansion segments, yet the protein inventories of their ribosomes do not radically differ from the species possessing canonical ribosomal RNAs. We also show that the loss of expansion segments occurred independently in several phylogenetic lineages of yeasts pointing out their dispensable nature. The differences identified in yeast ribosomal RNAs open a venue for further studies of these enigmatic elements of the eukaryotic ribosome.
Pinpoint: trajectory planning for multi-probe electrophysiology and injections in an interactive web-based 3D environment
Authors: Birman Daniel , Yang Kenneth J. , West Steven J. , Karsh Bill , Browning Yoni ,   the International Brain Laboratory, Siegle Joshua H. , Steinmetz Nicholas A. 
Published: July 2023

AbstractTargeting deep brain structures during electrophysiology and injections requires intensive training and expertise. Even with experience, researchers often can’t be certain that a probe is placed precisely in a target location and this complexity scales with the number of simultaneous probes used in an experiment. Here, we presentPinpoint, open-source software that allows for interactive exploration of stereotaxic insertion plans. Once an insertion plan is created, Pinpoint allows users to save these online and share them with collaborators. 3D modeling tools allow users to explore their insertions alongside rig and implant hardware and ensure plans are physically possible. Probes in Pinpoint can be linked to electronic micro-manipulators allowing real-time visualization of current brain region targets alongside neural data. In addition, Pinpoint can control manipulators to automate and parallelize the insertion process. Compared to previously available software, Pinpoint’s easy access through web browsers, extensive features, and real-time experiment integration enable more efficient and reproducible recordings.
Overcoming Resolution Attenuation During Tilted Cryo-EM Data Collection
Authors: Aiyer Sriram , Baldwin Philip R. , Tan Shi Min , Shan Zelin , Oh Juntaek , Mehrani Atousa , Bowman Marianne E , Louie Gordon , Passos Dario Oliveira , Đorđević-Marquardt Selena , Mietzsch Mario , Hull Joshua A. , Hoshika Shuichi , Barad Benjamin A. , Grotjahn Danielle A. , McKenna Robert , Agbandje-McKenna Mavis , Benner Steven A. , Noel Joseph A. P. , Wang Dong , Tan Yong Zi , Lyumkis Dmitry 
Published: July 2023

AbstractStructural biology efforts using cryogenic electron microscopy are frequently stifled by specimens adopting “preferred orientations” on grids, leading to anisotropic map resolution and impeding structure determination. Tilting the specimen stage during data collection is a generalizable solution but has historically led to substantial resolution attenuation. Here, we develop updated data collection and image processing workflows and demonstrate, using multiple specimens, that resolution attenuation is negligible or significantly reduced across tilt angles. Reconstructions with and without the stage tilted as high as 60° are virtually indistinguishable. These strategies allowed the reconstruction to 3 Å resolution of a bacterial RNA polymerase with preferred orientation. Furthermore, we present a quantitative framework that allows cryo-EM practitioners to define an optimal tilt angle for dataset acquisition. These data reinforce the utility of employing stage tilt for data collection and provide quantitative metrics to obtain isotropic maps.
Transcriptomic response in pyroxsulam-resistant and susceptibleBromus sterilisidentified three distinct mechanisms of resistance
Authors: Sen Madhab Kumar , Hamouzová Katerina , Onkokesung Nawaporn , Menendez Julio , Torra Joel , Košnarová Pavlina , Sellamuthu Gothandapani , Gupta Aayushi , Bharati Rohit , Sur Vishma Pratap , Roy Amit , Soukup Josef 
Published: July 2023

AbstractBromus sterilishas evolved into a more predominant weed in the Czech Republic’s winter wheat fields, owing largely to the widespread application of pyroxsulam for its management. In this study, we report a biotype that has developed resistance to pyroxsulam and has also shown cross- resistance to other herbicides. Although no differences in ploidy levels or no mutations of acetolactate synthase (ALS) were detected, a significant elevation of ALS enzyme activity was observed in the R biotype. Through combined analysis of enzyme inhibition and total transcript expression (RNA-Seq), we have identified differentially expressed transcripts that potentially contribute to pyroxsulam metabolism. Furthermore, we observed a significant increase in the expression of genes involved in redox mechanisms and transporters that could contribute to enhanced resistance to pyroxulam in the R biotype. Our results present a novel understanding of herbicide resistance inB. sterilisthrough three distinct resistance mechanisms (ALSgene overexpression, enhanced metabolism and reduced translocation) without mutation in the herbicide target protein. This understanding is the foundation for improving management strategies for herbicide resistantB. sterilis.
Phosphorylation modulates estrogen receptor disorder by altering long-range hydrophobic interactions
Authors: Du Zhanwen , Wang Han , Wu Chen , Buck Matthias , Zheng Wenwei , Hansen Alexandar L. , Kao Hung-Ying , Yang Sichun 
Published: July 2023

AbstractProtein intrinsic disorder is coupled to a range of biological phenomena, from gene regulation to cancer progression. Phosphorylation of the estrogen receptor (ER) at Ser118 through its disordered N-terminal domain (NTD) activates its transcriptional function, but it is challenging to rationalize how this modification regulates ER activity. Using biophysical approaches of small-angle X-ray scattering and nuclear magnetic resonance spectroscopy, we demonstrate that Ser118 phosphorylation triggers long-range conformational changes in ER-NTD, particularly between two hydrophobic clusters of residual structures. Alanine substitution of hydrophobic amino acids near Ser118 produces similar conformational alterations and rescues impaired ER activity caused by a phosphorylation-deficient mutant. These findings establish a direct link between phosphorylation-induced conformational changes and the activation function of this disordered protein as a promising avenue to block ER transcriptional activation.
Reinforcement learning-guided control strategies for CAR T-cell activation and expansion
Authors: Ferdous Sakib , Shihab Ibne Farabi , Chowdhury Ratul , Reuel Nigel F. 
Published: July 2023

AbstractReinforcement learning (RL), a subset of machine learning (ML), can potentially optimize and control biomanufacturing processes, such as improved production of therapeutic cells. Here, the process of CAR-T cell activation by antigen presenting beads and their subsequent expansion is formulatedin-silico. The simulation is used as an environment to train RL-agents to dynamically control the number of beads in culture with the objective of maximizing the population of robust effector cells at the end of the culture. We make periodic decisions of incremental bead addition or complete removal. The simulation is designed to operate in OpenAI Gym which enables testing of different environments, cell types, agent algorithms and state-inputs to the RL-agent. Agent training is demonstrated with three different algorithms (PPO, A2C and DQN) each sampling three different state input types (tabular, image, mixed); PPO-tabular performs best for this simulation environment. Using this approach, training of the RL-agent on different cell types is demonstrated, resulting in unique control strategies for each type. Sensitivity to input noise (sensor performance), number of control step interventions, and advantage of pre-trained agents are also evaluated. Therefore, we present a general computational framework to maximize the population of robust effector cells in CAR-T cell therapy production.Author SummaryCustom control strategies for expansion and activation of patient-specific CAR T-cell therapies resolved by reinforcement learning using a simulation environment and updatable cell growth parameters.
Rapid identification of key genes for the rod-shaped morphology in bacteria using multi-species genomes
Authors: Liu Qi , Liu Haida , Xu Chuangchuang , Shi Jianqiang , Xie Yanghe , Hu Shunli , Han Guomin 
Published: July 2023

AbstractAccurate identification of key genes is pivotal in biological research. Here, we introduce machine learning to the field of functional gene identification, enabling precise prediction of bacterial shape based on genomic information. Our machine learning model successfully predicts bacterial shape, and we determine the influence of various protein domains on shape using the model. This approach facilitates the identification of candidate genes involved in regulating bacterial shape. Through targeted knockout experiments on eight potential key regulatory genes (pal, yicC, mreB, tolQ, ftsX, amiC, yddB, andrpoZ) inEscherichia coli, we observe significant alterations in rod-shaped morphology upon individual knockout ofpalandmreBgenes.E. colitransitions from rod-shaped to spherical or cell wall-deficient protoplasmic states. Experimental validations validate the robustness of our newly developed method. This study establishes an innovative avenue for exploring functional genes, harnessing large-scale genomic information to promptly uncover key genes governing shared traits across species.
Tyk2-mediated signaling promotes the development of autoreactive CD8+CTLs and autoimmune type 1 diabetes
Authors: Mine Keiichiro , Nagafuchi Seiho , Akazawa Satoru , Abiru Norio , Mori Hitoe , Kurisaki Hironori , Yoshikai Yasunobu , Takahashi Hirokazu , Anzai Keizo 
Published: July 2023

ABSTRACTTyrosine kinase 2 (TYK2), a member of the JAK family, might be a susceptibility gene for type 1 diabetes (T1D), whereas its precise role in autoimmune T1D remains unknown. We showedTyk2deficiency and inhibition suppressed autoimmune T1D development in non-obese diabetic (NOD) mice. Defective IL-12 signaling due toTyk2deficiency in islet-autoreactive CD8+CTLs during their priming reduced T-bet expression, leading to impaired Cxcr3 expression and effector functions against β-cells.Tyk2deficient CD8+resident dendritic cells (rDC) exhibited reduced MHC I expression and impaired cross-priming of CTLs. In β-cells, increased expressions ofFas, MHC I, and chemokines with age were attenuated byTyk2deficiency. We demonstrated that treatment with BMS-986165, a Tyk2 inhibitor, inhibited the development of CTLs and inflammation in β-cellsin vitro. BMS-986165 reduced the incidence of diabetes in NOD mice. Thus, we demonstrated that Tyk2-mediated signaling has a critical role in the development of autoreactive CD8+CTLs, inflammation in β-cells, and the pathogenesis of autoimmune T1D.SummaryWe demonstrated that Tyk2-mediated signaling plays a critical role in the development of autoreactive CD8+CTLs, inflammation in β-cells, and the pathogenesis of autoimmune T1D. These findings will lead to the development of safety and effective prevention strategies for T1D.
KDM4-dependent DNA breaks at active promoters facilitate +1 nucleosome eviction
Authors: Imre László , Nánási Péter , Szatmári István , Kókai Endre , Austin Caroline A. , Dombrádi Viktor , Szabó Gábor 
Published: July 2023

AbstractWhen the effect of various posttranslational histone tail modifications (PTMs) on nucleosome stability was compared in anin situassay involving agarose-embedded nuclei, the promoter proximal H3K4me3, H3K27ac and H4K8ac positive nucleosomes exhibited relative sensitivity to intercalators as compared to bulk H3-GFP or nucleosomes carrying any of the following marks: H3K27me1, H3K27me2, H3K27me3, H3K9me1, H3K9me2, H3K9me3, H3K36me3, H3K4me0, H3K4me1, H3K4me2, H3K9ac, and H3K14ac. Nickase or DNase I treatment of the nuclei, or bleomycin treatment of live cells, did not affect the stability of nucleosomes carrying H3K4me3 or H3K27ac, while those of the second group were all destabilized upon treatment with intercalators. These observations support the possibility that the promoter proximal marks specify dynamic nucleosomes accomodating relaxed DNA sequences due to DNA breaks generatedin vivo. In line with this interpretation, endogeneous, 3’OH nicks were mapped within the nucleosome free region of promoters controlling genes active in human mononuclear cells, a conclusion supported by superresolution colocalization studies. The +1 nucleosomes were stabilized and the incidence of nicks was decreased at the promoters upon KDM4a,b,c KO induction (Pedersen et al, EMBO J, 2016) in mouse embryonic stem cells (mES). While etoposide did not further destabilize +1 nucleosomes in control mES, their stabilized state in the KO state was reversed by the drug. A significant fraction of the DNA breaks comprises TOP2-generated nicks according to the results of molecular combing experiments. The chromatin regions harboring nicks are topologicaly separated from the domains containing superhelical chromatin. These observations lend support for a model where the role of DNA strand discontinuities in transcriptional regulation and in higher-order chromatin organization are integrated.