bluuebunny/crossref_metadata_2025_split huggingface dataset:
Micelle-like clusters in phase-separated Nanog condensates: A molecular simulation study
Authors: Mizutani Azuki , Tan Cheng , Sugita Yuji , Takada Shoji 
Published: May 2023

AbstractThe phase separation model for transcription suggests that transcription factors (TFs), coactivators, and RNA polymerases form biomolecular condensates around active gene loci and regulate transcription. However, the structural details of condensates remain elusive. In this study, for Nanog, a master TF in mammalian embryonic stem cells known to form protein condensatesin vitro, we examined protein structures in the condensates using residue-level coarse-grained molecular simulations. Human Nanog formed micelle-like clusters in the condensate. In the micelle-like cluster, the C-terminal disordered domains, including the tryptophan repeat (WR) regions, interacted with each other near the cluster center primarily via hydrophobic interaction. In contrast, hydrophilic disordered N-terminal and DNA-binding domains were exposed on the surface of the clusters. Electrostatic attractions of these surface residues were responsible for bridging multiple micelle-like structures in the condensate. The micelle-like structure and condensate were dynamic and liquid-like. Mutation of tryptophan residues in the WR region which was implicated to be important for a Nanog function resulted in dissolution of the Nanog condensate. Finally, to examine the impact of Nanog cluster to DNA, we added DNA fragments to the Nanog condensate. Nanog DNA-binding domains exposed to the surface of the micelle-like cluster could recruit more than one DNA fragments, making DNA-DNA distance shorter.Author summaryIn eukaryotic transcription regulation, enhancer elements far from the promoter are known to modulate transcriptional activity, but the molecular mechanism remains elusive. One of these models, the phase separation model, suggests that transcription factors (TFs), coactivators, and transcription machinery form biomolecular condensates that include enhancer and promoter elements, making enhancer-promoter communication possible via the protein network in the condensate. Nanog, one of the core TFs involved in mammalian embryonic stem cells, has been reported to have the ability to form condensates. In this study, we addressed the structural details of Nanog condensates by performing residue-level coarse-grained molecular simulations. We found that Nanog formed micelle-like clusters via primarily hydrophobic interactions between tryptophan repeat regions in the C-terminal disordered domains within the condensate. On the other hand, highly charged N-terminal and DNA-binding domains were exposed to the surface of the micelle and were responsible for bridging many micelles into a condensate. The micelle-like clusters and condensate were dynamic and liquid-like. In addition, Nanog condensates could induce DNA-DNA attraction mediated by micelle-like structures.
Causes for and consequences of winning intergroup encounters in colobus monkeys (Colobus vellerosus)
Authors: Wikberg Eva C. , Lucci Sara , Glotfelty Emily , Campos Fernando , Sicotte Pascale 
Published: May 2023

AbstractThe outcome of an intergroup encounter depends on the relative competitive abilities of the participating groups and the value of the resource for which they compete. However, few studies have been able to assess the consequences of winning intergroup encounters. We used behavioral and demographic data from 94 adult and subadult individuals in 8 groups ofColobus vellerosusat Boabeng-Fiema, Ghana to investigate the factors that predict winning intergroup encounters, and whether intergroup encounter success determines access to food and female reproductive output. In support of the hypothesis that groups with high-quality males would be more likely to win encounters, winning the encounter was best predicted by rates of displays by the alpha male. Food trees that were contested during intergroup encounters were more likely to have young leaves or other higher quality food items and to be important food species. Feeding was more likely to occur during and after the intergroup encounter if the focal animal’s group had won the encounter. The percentage of encounters won was correlated with the group’s dominance rank but not with home range size or the immature-to-female ratio. In populations such as the Boabeng-Fiema colobus in which male quality seems to be associated with winning intergroup encounters and gaining immediate access to food, one of the drivers for female transfer between groups may be differences in alpha male quality between groups and across time.
On the role of melanistic coloration on thermoregulation in the crepuscular geckoEublepharis macularius
Authors: Hastings Brandon T. , Melnyk Anastasiya , Ghyabi Mehrdad , White Emma , Barroso Frederico M. , Carretero Miguel A , Lattanzi David , Claude Julien , Chiari Ylenia 
Published: May 2023

ABSTRACTBody coloration in ectotherms serves multiple biological functions, including avoiding predators, communicating with conspecific individuals, and involvement in thermoregulation. As ectotherms rely on environmental sources of heat to regulate their internal body temperature, stable melanistic body coloration or color change can be used to increase or decrease heat absorption and heat exchange with the environment. While the function of melanistic coloration for thermoregulation has been found to increase solar radiation absorption for heating in many diurnal ectotherms, research on crepuscular and nocturnal ectotherms is lacking. Since crepuscular and nocturnal ectotherms generally absorb heat from the substrate, coloration is likely under different selective pressures than in diurnal ectotherms. We tested if the proportion of dorsal melanistic body coloration is related to differences in body temperature heating and cooling rates in the crepuscular geckoEublepharis maculariusand whether changes in environmental temperature trigger color changes in this species. Temperature measurements of the geckos and of the environment were taken using infrared thermography and temperature loggers. Color data were obtained using objective photography and a newly developed custom software package. We found that body temperature reflected substrate temperatures, and that the proportion of melanistic coloration has no influence on heating or cooling rates or on color changes. These findings suggest that, inE. macularius, melanistic coloration may not be used for thermoregulation. Future research should further test the function of melanistic coloration in other crepuscular and nocturnal vertebrates to understand the evolution of melanistic pattern in animals active in low light conditions.
Epstein-Barr virus miR-BARTs 7 and 9 modulate viral cycle, cell proliferation and proteomic profiles in Burkitt lymphoma
Authors: Caetano Brunno Felipe Ramos , Rocha Viviana Loureiro , Rossini Bruno Cesar , Santos Lucilene Delazari dos , de Oliveira Deilson Elgui 
Published: May 2023

AbstractThe Epstein-Barr Virus (EBV) encodes viral microRNAs (miRs) that contribute to the pathogenesis of nasopharyngeal and gastric carcinomas, but their potential roles in lymphomas are still to be elucidated. This study sought to assess the impact of knocking down EBV miRs BART 7 and BART9 in EBV-positive Akata cell lines using CRISPR/Cas9 technology. Compared to cells harboring the wild-type (WT) EBV genomes, Akata cells subjected to CRISPR/Cas9-mediated knockdown of EBV BART 7 and BART9 showed a significant reduction in the expression of viral miRs, confirming the validity of the experimental model. Knocking down both BART7 and BART9 caused a significant reduction in cell viability and proliferation rates while increasing the expression of EBV lytic genes. Global proteomic analysis shows that knocking down EBV BART7 significantly decreased the expression of ubiquitin/proteasome proteins while increasing RNA binding proteins (RBPs). On the other hand, BART9 knockdown caused a decrease in proteins associated with oxidoreductase activity, including the metabolism of fatty acids. Our results unravel previously unknown roles for EBV miRs BART7 and BART9 on cellular pathways relevant to both viral biology and lymphomagenesis.
Regulation of RNA methylation by therapy treatment, promotes tumor survival
Authors: Bukhari Syed IA , Truesdell Samuel S , Datta Chandreyee , Choudhury Pritha , Wu Keith Q , Shrestha Jitendra , Maharjan Ruby , Plotsker Ethan , Elased Ramzi , Laisa Sadia , Bhambhani Vijeta , Lin Yue , Kreuzer Johannes , Morris Robert , Koh Siang-Boon , Ellisen Leif W. , Haas Wilhelm , Ly Amy , Vasudevan Shobha 
Published: May 2023

AbstractOur data previously revealed that chemosurviving cancer cells translate specific genes. Here, we find that the m6A-RNA-methyltransferase, METTL3, increases transiently in chemotherapy-treated breast cancer and leukemic cells in vitro and in vivo. Consistently, m6A increases on RNA from chemo-treated cells, and is needed for chemosurvival. This is regulated by eIF2α phosphorylation and mTOR inhibition upon therapy treatment. METTL3 mRNA purification reveals that eIF3 promotes METTL3 translation that is reduced by mutating a 5′UTR m6A-motif or depleting METTL3. METTL3 increase is transient after therapy treatment, as metabolic enzymes that control methylation and thus m6A levels on METTL3 RNA, are altered over time after therapy. Increased METTL3 reduces proliferation and anti-viral immune response genes, and enhances invasion genes, which promote tumor survival. Consistently, overriding phospho-eIF2α prevents METTL3 elevation, and reduces chemosurvival and immune-cell migration. These data reveal that therapy-induced stress signals transiently upregulate METTL3 translation, to alter gene expression for tumor survival.One sentence summarym6A enzyme translation upon therapy stress, promotes tumor survival
Disrupted memory T cell expansion in HIV-exposed uninfected infants is preceded by premature skewing of T cell receptor clonality
Authors: Dzanibe Sonwabile , Wilk Aaron J. , Canny Susan , Ranganath Thanmayi , Alinde Berenice , Rubelt Florian , Huang Huang , Davis Mark M. , Holmes Susan , Jaspan Heather B. , Blish Catherine A. , Gray Clive M. 
Published: May 2023

AbstractWhile preventing vertical HIV transmission has been very successful, the increasing number of HIV-exposed uninfected infants (iHEU) experience an elevated risk to infections compared to HIV-unexposed and uninfected infants (iHUU). Immune developmental differences between iHEU and iHUU remains poorly understood and here we present a longitudinal multimodal analysis of infant immune ontogeny that highlights the impact of HIV/ARV exposure. Using mass cytometry, we show alterations and differences in the emergence of NK cell populations and T cell memory differentiation between iHEU and iHUU. Specific NK cells observed at birth were also predictive of acellular pertussis and rotavirus vaccine-induced IgG and IgA responses, respectively, at 3 and 9 months of life. T cell receptor Vβ clonotypic diversity was significantly and persistently lower in iHEU preceding the expansion of T cell memory. Our findings show that HIV/ARV exposure disrupts innate and adaptive immunity from birth which may underlie relative vulnerability to infections.
Longitudinal analysis of a dietary mouse model of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)
Authors: Saenz Marissa , McDonough Jillian C. , Bloom-Saldana Elizabeth , Irimia Jose M. , Cauble Emily L. , Castillo Ashly , Fueger Patrick T. , Treviño Lindsey S. 
Published: May 2023

ABSTRACTNon-alcoholic fatty liver disease (NAFLD), and resultant non-alcoholic steatohepatitis (NASH), incidence and prevalence are rising globally due to increasing rates of obesity and diabetes. Currently, there are no approved pharmacological treatments for NAFLD, highlighting a need for additional mechanistic studies to develop prevention and/or therapeutic strategies. Diet-induced preclinical models of NAFLD can be used to examine the dynamic changes that occur during NAFLD development and progression throughout the lifespan. To date, most studies utilizing such models have focused exclusively on terminal time points and have likely missed critical early and late changes that are important for NAFLD progression (i.e, worsening). We performed a longitudinal analysis of histopathological, biochemical, transcriptomic, and microbiome changes that occurred in adult male mice fed either a control diet or a NASH-promoting diet (high in fat, fructose, and cholesterol) for up to 30 weeks. We observed progressive development of NAFLD in mice fed the NASH diet compared to the control diet. Differential expression of immune-related genes was observed at an early stage of diet-induced NAFLD development (10 weeks) and persisted into the later stages of the disease (20 and 30 weeks). Differential expression of xenobiotic metabolism related genes was observed at the late stage of diet-induced NAFLD development (30 weeks). Microbiome analysis revealed an increased abundance ofBacteroidesat an early stage (10 weeks) that persisted into the later stages of the disease (20 and 30 weeks). These data provide insight into the progressive changes that occur during NAFLD/NASH development and progression in the context of a typical Western diet. Furthermore, these data are consistent with what has been reported in patients with NAFLD/NASH, supporting the preclinical use of this diet-induced model for development of strategies to prevent or treat the disease.
Predicting gene level sensitivity to JAK-STAT signaling perturbation using a mechanistic-to-machine learning framework
Authors: Cheemalavagu Neha , Shoger Karsen E. , Cao Yuqi M. , Michalides Brandon A. , Botta Samuel A. , Faeder James R. , Gottschalk Rachel A. 
Published: May 2023

AbstractThe JAK-STAT pathway integrates complex cytokine signals via a limited number of molecular components, inspiring numerous efforts to clarify the diversity and specificity of STAT transcription factor function. We developed a computational workflow to make global cytokine-induced gene predictions from STAT phosphorylation dynamics, modeling macrophage responses to IL-6 and IL-10, which signal through common STATs, but with distinct temporal dynamics and contrasting functions. Our mechanistic-to-machine learning model identified select cytokine-induced gene sets associated with late pSTAT3 timeframes and a preferential pSTAT1 reduction upon JAK2 inhibition. We predicted and validated the impact of JAK2 inhibition on gene expression, identifying dynamically regulated genes that were sensitive or insensitive to JAK2 variation. Thus, we successfully linked STAT signaling dynamics to gene expression to support future efforts targeting pathology-associated STAT-driven gene sets. This serves as a first step in developing multi-level prediction models to understand and perturb gene expression outputs from signaling systems.
CRISPR-based engineering of RNA viruses
Authors: Nemudryi Artem , Nemudraia Anna , Nichols Joseph E , Scherffius Andrew M , Zahl Trevor , Wiedenheft Blake 
Published: May 2023

AbstractCRISPR RNA-guided endonucleases have enabled precise editing of DNA. However, options for editing RNA remain limited. Here, we combine sequence-specific RNA cleavage by CRISPR ribonucleases with programmable RNA repair to make precise deletions and insertions in RNA. This work establishes a new recombinant RNA technology with immediate applications for the facile engineering of RNA viruses.One-Sentence SummaryProgrammable CRISPR RNA-guided ribonucleases enable recombinant RNA technology.
The structure of NAD+consuming proteinAcinetobacter baumanniiTIR domain shows unique kinetics and conformations
Authors: Klontz Erik , Obi Juliet O. , Wang Yajing , Glendening Gabrielle , Carr Jahid , Tsibouris Constantine , Buddula Sahthi , Nallar Shreeram , Soares Alexei S. , Beckett Dorothy , Redzic Jasmina S. , Eisenmesser Elan , Palm Cheyenne , Schmidt Katrina , Scudder Alexis H. , Obiorah Trinity , Essuman Kow , Milbrandt Jeffrey , Diantonio Aaron , Ray Krishanu , Deredge Daniel , Snyder M LD. , Snyder Greg A. 
Published: May 2023

AbstractToll-like and Interleukin-1/18 receptor resistance (TIR) domain-containing proteins function as important signaling and immune regulatory molecules. TIR domain-containing proteins identified in eukaryotic and prokaryotic species also exhibit NAD+ hydrolase activity in select bacteria, plants, and mammalian cells. We report the crystal structure of theAcinetobacter baumanniiTIR domain protein (AbTir-TIR) with confirmed NAD+hydrolysis and map the conformational effects of its interaction with NAD+using HDX-MS. NAD+results in mild decreases in deuterium uptake at the dimeric interface. In addition, AbTir-TIR exhibits EX1 kinetics indicative of large cooperative conformational changes which are slowed down upon substrate binding. Additionally, we have developed label-free imaging using 2pFLIM which shows differences in bacteria expressing native and mutant NAD+ hydrolase-inactivated AbTir-TIREAprotein. Our observations are consistent with substrate-induced conformational changes reported in other TIR model systems with NAD+ hydrolase activity. These studies provide further insight into bacterial TIR protein mechanisms and their varying roles in biology.
Centralin vivomechanisms by whichC. difficile’sproline reductase drives efficient metabolism, growth, and toxin production
Authors: Cersosimo Laura M. , Graham Madeline , Monestier Auriane , Pavao Aidan , Worley Jay N. , Peltier Johann , Dupuy Bruno , Bry Lynn 
Published: May 2023

AbstractClostridioides difficile(CD) is a sporulating and toxin-producing nosocomial pathogen that opportunistically infects the gut, particularly in patients with depleted microbiota after antibiotic exposure. Metabolically, CD rapidly generates energy and substrates for growth from Stickland fermentations of amino acids, with proline being a preferred reductive substrate. To investigate thein vivoeffects of reductive proline metabolism onC.difficile’svirulence in an enriched gut nutrient environment, we evaluated wild-type and isogenicΔprdBstrains of ATCC43255 on pathogen behaviors and host outcomes in highly susceptible gnotobiotic mice. Mice infected with theΔprdBmutant demonstrated extended survival via delayed colonization, growth and toxin production but ultimately succumbed to disease.In vivotranscriptomic analyses demonstrated how the absence of proline reductase activity more broadly disrupted the pathogen’s metabolism including failure to recruit oxidative Stickland pathways, ornithine transformations to alanine, and additional pathways generating growth-promoting substrates, contributing to delayed growth, sporulation, and toxin production. Our findings illustrate the central role for proline reductase metabolism to support early stages ofC. difficilecolonization and subsequent impact on the pathogen’s ability to rapidly expand and cause disease.
How do fluctuating temperatures alter the cost of development?
Authors: Pettersen Amanda K , Nord Andreas , While Geoffrey , Uller Tobias 
Published: May 2023

AbstractQuantifying how variable temperature regimes affect energy expenditure during development is crucial for understanding how future thermal regimes may impact early life survival and population persistence.Developmental Cost Theory (DCT) suggests that there is an optimal temperature (Topt) that minimises energy expenditure during development (the “cost of development”). Exposure to fluctuating temperatures around an average of Toptare anticipated to increase either development time or metabolic rate. As a result, embryos will rapidly deplete yolk reserves, and consequently hatch at a smaller size or with less residual yolk to support postnatal survival and growth.Here, we studied total embryonic energy expenditure (development time and rate of CO2production) and conversion of yolk into tissue in common wall lizards (Podarcis muralis) under three incubation treatments anticipated, based on DCT, to increase the cost of development: no variance (Toptconstant, 24 °C), low variance (22 – 26 °C), and high variance (18 – 30 °C).As predicted, we found that increasing variance around Toptincreased the cost of development, despite reducing time to hatching. As a consequence, embryos on average hatched with 59% lower residual yolk reserves under high variance versus constant incubation temperatures.Our results highlight how the relative temperature sensitivities of development time and metabolic rate determine the cost of development, which in turn may predict the ability of egg-laying ectotherms to persist in variable environments. We show that DCT can provide a mechanistic framework for understanding the widespread, but often seemingly idiosyncratic, effects of fluctuating incubation temperatures on hatchling tissue and residual yolk mass.
Cancer cells co-evolve with retrotransposons to mitigate viral mimicry
Authors: Sun Siyu , Hong Jungeui , You Eunae , Tsanov Kaloyan M. , Chacon-Barahona Jonathan , Gioacchino Andrea Di , Hoyos David , Li Hao , Jiang Hua , Ly Han , Marhon Sajid , Murali Rajmohan , Chanda Pharto , Karacay Ali , Vabret Nicolas , De Carvalho Daniel D. , LaCava John , Lowe Scott W. , Ting David T. , Iacobuzio-Donahue Christine A. , Solovyov Alexander , Greenbaum Benjamin D. 
Published: May 2023

ABSTRACTOverexpression of repetitive elements is an emerging hallmark of human cancers1. Diverse repeats can mimic viruses by replicating within the cancer genome through retrotransposition, or presenting pathogen-associated molecular patterns (PAMPs) to the pattern recognition receptors (PRRs) of the innate immune system2–5. Yet, how specific repeats affect tumor evolution and shape the tumor immune microenvironment (TME) in a pro- or anti-tumorigenic manner remains poorly defined. Here, we integrate whole genome and total transcriptome data from a unique autopsy cohort of multiregional samples collected in pancreatic ductal adenocarcinoma (PDAC) patients, into a comprehensive evolutionary analysis. We find that more recently evolvedShortInterspersedNuclearElements (SINE), a family of retrotransposable repeats, are more likely to form immunostimulatory double-strand RNAs (dsRNAs). Consequently, younger SINEs are strongly co-regulated with RIG-I like receptor associated type-I interferon genes but anti-correlated with pro-tumorigenic macrophage infiltration. We discover that immunostimulatory SINE expression in tumors is regulated by eitherLongInterspersedNuclearElements 1 (LINE1/L1) mobility or ADAR1 activity in aTP53mutation dependent manner. Moreover, L1 retrotransposition activity tracks with tumor evolution and is associated withTP53mutation status. Altogether, our results suggest pancreatic tumors actively evolve to modulate immunogenic SINE stress and induce pro-tumorigenic inflammation. Our integrative, evolutionary analysis therefore illustrates, for the first time, how dark matter genomic repeats enable tumors to co-evolve with the TME by actively regulating viral mimicry to their selective advantage.