bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting transcription factors through an IMiD independent zinc finger domain
Authors: Liu Bee Hui , Liu Miao , Radhakrishnan Sridhar , Jaladanki Chaitanya Kumar , Gao Chong , Tang Jing Ping , Kumari Kalpana , Go Mei Lin , Vu Kim Anh L. , Seo Hyuk-Soo , Song Kijun , Tian Xi , Feng Li , Tan Justin L. , Bassal Mahmoud A. , Arthanari Haribabu , Qi Jun , Dhe-Paganon Sirano , Fan Hao , Tenen Daniel G. , Chai Li 
Published: January 2024

AbstractImmunomodulatory imide drugs (IMiDs) degrade specific C2H2 zinc finger degrons in transcription factors, making them effective against certain cancers. SALL4, a cancer driver, contains seven C2H2 zinc fingers in four clusters, including an IMiD degron in zinc finger cluster two (ZFC2). Surprisingly, IMiDs do not inhibit growth of SALL4 expressing cancer cells. To overcome this limit, we focused on a non-IMiD degron, SALL4 zinc finger cluster four (ZFC4). By combining AlphaFold and the ZFC4-DNA crystal structure, we identified a potential ZFC4 drug pocket. Utilizing anin silicodocking algorithm and cell viability assays, we screened chemical libraries and discovered SH6, which selectively targets SALL4-expressing cancer cells. Mechanistic studies revealed that SH6 degrades SALL4 protein through the CUL4A/CRBN pathway, while deletion of ZFC4 abolished this activity. Moreover, SH6 led to significant 62% tumor growth inhibition of SALL4+ xenografts in vivo and demonstrated good bioavailability in pharmacokinetic studies. In summary, these studies represent a new approach for IMiD independent drug discovery targeting C2H2 transcription factors in cancer.Graphical Abstract
Two Distinct Regulatory Systems Control Pulcherrimin Biosynthesis inBacillus subtilis
Authors: Fernandez Nicolas L. , Simmons Lyle A. 
Published: January 2024

AbstractRegulation of transcription is a fundamental process that allows bacteria to respond to external stimuli with appropriate timing and magnitude of response. In the soil bacteriumBacillus subtilis,transcriptional regulation is at the core of developmental processes needed for cell survival. Gene expression in cells transitioning from exponential phase to stationary phase is under the control of a group of transcription factors called transition state regulators (TSRs). TSRs influence numerous developmental processes including the decision between biofilm formation and motility, genetic competence, and sporulation, but the extent to which TSRs influence bacterial physiology remains to be fully elucidated. Here, we demonstrate two TSRs, ScoC and AbrB, along with the MerR-family transcription factor PchR negatively regulate production of the iron chelator pulcherrimin inB. subtilis.Genetic analysis of the relationship between the three transcription factors indicate that all are necessary to limit pulcherrimin production during exponential phase and influence the rate and total amount of pulcherrimin produced. Similarly, expression of the pulcherrimin biosynthesis geneyvmCwas found to be under control of ScoC, AbrB, and PchR and correlated with the amount of pulcherrimin produced by each background. Lastly, our in vitro data indicate a weak direct role for ScoC in controlling pulcherrimin production along with AbrB and PchR. The layered regulation by two distinct regulatory systems underscores the important, and somewhat enigmatic, role for pulcherrimin inB. subtilisphysiology.Author SummaryRegulation of gene expression is important for survival in ever changing environments. In the soil bacteriumBacillus subtilis,key developmental processes are controlled by overlapping networks of transcription factors, some of which are termed transition state regulators (TSRs). Despite decades of research, the scope of how TSRs influenceB. subtilisphysiology is still being uncovered. We found that three transcription factors, two of which are TSRs, converge to inhibit production of the iron-chelator pulcherrimin. Only when all three are missing is pulcherrimin production elevated. Finally, we demonstrate that expression of pulcherrimin biosynthesis genes occurs via direct and indirect regulation by the trio of transcription factors. Due to its iron chelating ability, pulcherrimin has been characterized as a modulator of niche development with antioxidant properties. Thus, our findings that TSRs control pulcherrimin, concurrently with other developmental phenotypes, provides new insight into how TSRs impactB. subtilisand its interaction with the environment.
Differences in selective profiles among single or double stranded DNA or RNA viruses. Statistical detection of its double or single stranded condition
Authors: Valenzuela Carlos Y 
Published: January 2024

ABSTRACTI developed a test to study the probability distribution of bases in dinucleotides separated by 0, 1, 2…K nucleotides sites. This analysis define selective profiles of dinucleotides by their sign and selection coefficients, their distance to neutrality measured by a chi-square value and the order of significance of their distance to randomness among the 16 possible values. In double stranded (ds) DNA or RNA an index (index = I, with 5’-3’ sense) dinucleotide participates in evolutionary processes together with three dinucleotides defined by base complementarity and 5’-3’ sense. The anti-sense dinucleotide in the same strand, the parallel (Par, with 3’-5’ sense) and anti-parallel (a-Par, with 5’-3’ sense) dinucleotides in the complementary strand. Single stranded (ss) RNA or DNA do not have these set of dinucleotides and would not present similarities or differences, among those four dinucleotides. I studied viromes taken from GenBank, with ds and ss RNA and DNA by this dinucleotide analysis. The core matrix has rows with Separations (Sep) of bases and columns with their selective profiles of the Index, Par and a-Par dinucleotides. Profiles distances I-Par and I-a-Par where compared. The ds RNA or DNA showed larger selective profiles differences between I-Par than I-a-Par. Ss RNA or DNA viruses showed non-significant differences between these comparisons. Those ss virus that exist as ds virus in their hosts, as Hindbis and HIV virus behaved similarly to ds viruses. Coli phage PhiX174 an ss DNA virus showed smaller I-Par than I-a-Par selective distances.IMPORTANCEI present a new method for the comparison of selective profiles that allows know whether a RNA or DNA behaves preferentially as ds or ss nucleic acid and gives information about their dynamic or evolutionary mechanisms of replication cycles. This changes our vision of viruses constituted in the virion as ds or ss viruses towards a functional evolutionary vision where viruses are ds and ss according to their behavior along with their life cycle. This evolutionary vision may be crucial in epidemiology.
Evaluation of Gremlin-1 as a therapeutic target in metabolic dysfunction-associated steatohepatitis
Authors: Horn Paul , Norlin Jenny , Almholt Kasper , Viuff Birgitte M. , Galsgaard Elisabeth D. , Hald Andreas , Zosel Franziska , Demuth Helle , Poulsen Svend , Norby Peder L. , Rasch Morten G. , Vyberg Mogens , Werge Mikkel Parsberg , Gluud Lise Lotte , Rink Marco R. , Shepherd Emma , Northall Ellie , Lalor Patricia F. , Weston Chris J. , Fog-Tonnesen Morten , Newsome Philip N. 
Published: January 2024

AbstractGremlin-1 has been implicated in liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH) via inhibition of bone-morphogenetic protein (BMP) signalling and has thereby been identified as a potential therapeutic target. Using ratin vivoand humanin vitroandex vivomodel systems of MASH fibrosis, we show that neutralisation of Gremlin-1 activity with monoclonal therapeutic antibodies does not reduce liver inflammation or liver fibrosis. Still, Gremlin-1 was upregulated in human and rat MASH fibrosis, but expression was restricted to a small subpopulation of COL3A1/THY1+myofibroblasts. Lentiviral overexpression of Gremlin-1 in LX-2 cells and primary hepatic stellate cells led to changes in BMP-related gene expression, which did not translate to increased fibrogenesis. Furthermore, we show that Gremlin-1 binds to heparin with high affinity, which prevents Gremlin-1 from entering systemic circulation, prohibiting Gremlin-1-mediated organ crosstalk. Overall, our findings suggest a redundant role for Gremlin-1 in the pathogenesis of liver fibrosis, which is unamenable to therapeutic targeting.
Ileal mucus viscoelastic properties differ in Crohn’s disease
Authors: Kramer Catharina , Rulff Hanna , Ziegler Jörn Felix , Alzain Nadra , Addante Annalisa , Kuppe Aditi , Timm Sara , Schrade Petra , Bischoff Philip , Glauben Rainer , Dürr Julia , Ochs Matthias , Mall Marcus A. , Gradzielski Michael , Siegmund Britta 
Published: January 2024

AbstractCrohn’s disease (CD) is an inflammatory bowel disease (IBD) that can affect any part of the gastrointestinal tract, frequently involving the terminal ileum. While colonic mucus alterations in CD patients have been described, terminal ileal mucus and its mechanobiological properties have been neglected. Our study is the first of its kind to decipher the viscoelastic and network properties of ileal mucus.With that aim, oscillatory rheological shear measurements based on an airway mucus protocol that was thoroughly validated for ileal mucus were performed. Our pilot study analyzed terminal ileum mucus from controls (n=11) and CD patients (n=11). Mucus network structure was visualized by scanning electron microscopy (SEM).Interestingly, a statistically significant increase in viscoelasticity as well as a decrease in mesh size was observed in ileal mucus from CD patients compared to controls. Furthermore, rheological data were analyzed in relation to study participants clinical characteristics, such as inflammatory status, revealing noteworthy trends.In conclusion, this study provides the first data on the viscoelastic properties and structure of human ileal mucus in the healthy state and in CD, demonstrating significant alterations between groups and highlighting the need for further research on mucus and its effect on the underlying epithelial barrier.
Differential activation of rhodopsin triggers distinct endocytic trafficking and recycling in vivo via differential phosphorylation
Authors: Ferng Darwin , Sun Wesley , Shieh Bih-Hwa 
Published: January 2024

ABSTRACTActivated GPCRs are phosphorylated and internalized mostly via clathrin-mediated endocytosis (CME), which are then sorted for recycling or degradation. We investigated how differential activation of the same GPCR affects its endocytic traffickingin vivousing rhodopsin as a model in flies expressing mCherry-tagged rhodopsin 1 (Rh1-mC) or GFP-tagged arrestin 1 (Arr1-GFP). Upon blue light stimulation, activated Rh1 recruited Arr1-GFP to the rhabdomere, which became co-internalized and accumulated in cytoplasmic vesicles of photoreceptors. This internalization was eliminated inshits1mutants affecting dynamin. Moreover, it was blocked by eitherrdgAorrdgBmutations affecting the PIP2biosynthesis. Together, the blue light-initiated internalization of Rh1 and Arr1 belongs to CME. Green light stimulation also triggered the internalization and accumulation of activated Rh1-mC in the cytoplasm but with faster kinetics. Importantly, Arr1-GFP was also recruited to the rhabdomere but not co-internalized with Rh1-mC. This endocytosis was not affected inshits1norrdgAmutants, indicating it is not CME. We explored the fate of internalized Rh1-mC following CME and observed it remained in cytoplasmic vesicles following 30 min of dark adaptation. In contrast, in the non-CME Rh1-mC appeared readily recycled back to the rhabdomere within five min of dark treatment. This faster recycling may be regulated by rhodopsin phosphatase, RdgC. Together, we demonstrate two distinct endocytic and recycling mechanisms of Rh1 via two light stimulations. It appears that each stimulation triggers a distinct conformation leading to different phosphorylation patterns of Rh1 capable of recruiting Arr1 to rhabdomeres. However, a more stable interaction leads to the co-internalization of Arr1 that orchestrates CME. A stronger Arr1 association appears to impede the recycling of the phosphorylated Rh1 by preventing the recruitment of RdgC. We conclude that conformations of activated rhodopsin determine the downstream outputs upon phosphorylation that confers differential protein-protein interactions.
Mitochondrial reverse electron transport in myeloid cells perpetuates neuroinflammation
Authors: Peruzzotti-Jametti L. , Willis C.M. , Hamel R. , Krzak G. , Reisz J.A. , Prag H.A. , Wu V. , Xiang Y. , van den Bosch A.M.R. , Nicaise A.M. , Roth L. , Bates G.R. , Huang H. , Vincent A.E. , Frezza C. , Viscomi C. , Marioni J.C. , D’Alessandro A. , Takats Z. , Murphy M.P. , Pluchino S. 
Published: January 2024

ABSTRACTSustained smouldering, or low grade, activation of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis (MS)1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells2. However, how these metabolic features act to perpetuate neuroinflammation is currently unknown. Using a multiomics approach, we identified a new molecular signature that perpetuates the activation of myeloid cells through mitochondrial complex II (CII) and I (CI) activity driving reverse electron transport (RET) and the production of reactive oxygen species (ROS). Blocking RET in pro-inflammatory myeloid cells protected the central nervous system (CNS) against neurotoxic damage and improved functional outcomes in animal disease modelsin vivo. Our data show that RET in myeloid cells is a potential new therapeutic target to foster neuroprotection in smouldering inflammatory CNS disorders3.
GM-CSF-mediated epithelial-immune cell crosstalk orchestrates pulmonary immunity toAspergillus fumigatus
Authors: Mills Kathleen A. M. , Westermann Frederike , Espinosa Vanessa , Rosiek Eric , Desai Jigar V. , Aufiero Mariano A. , Guo Yahui , Mitchell Kennedy A. , Tuzlak Selma , De Feo Donatella , Lionakis Michail S. , Rivera Amariliz , Becher Burkhard , Hohl Tobias M. 
Published: January 2024

SUMMARYAspergillus fumigatuscauses life-threatening mold pneumonia in immune compromised patients, particularly in those with quantitative or qualitative defects in neutrophils. While innate immune cell crosstalk licenses neutrophil antifungal activity in the lung, the role of epithelial cells in this process is unknown. Here, we find that that surfactant protein C (SPC)-expressing lung epithelial cells integrate infection-induced IL-1 and type III interferon signaling to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) preferentially at local sites of fungal infection and neutrophil influx. Usingin vivomodels that distinguish the role of GM-CSF during acute infection from its homeostatic function in alveolar macrophage survival and surfactant catabolism, we demonstrate that epithelial-derived GM-CSF increases the accumulation and fungicidal activity of GM-CSF-responsive neutrophils, with the latter being essential for host survival. Our findings establish SPC+epithelial cells as a central player in regulating the quality and strength of neutrophil-dependent immunity against inhaled mold pathogens.HIGHLIGHTSGM-CSF is essential for host defense againstA. fumigatusin the lungIL-1 and IFN-λ promote GM-CSF production by lung epithelial cells in parallelEpithelial cell-derived GM-CSF increases neutrophil accumulation and fungal killing capacityEpithelial cells preferentially upregulate GM-CSF in local sites of inflammationGRAPHICAL ABSTRACT
A Murine Model of Post-acute Neurological Sequelae Following SARS-CoV-2 Variant Infection
Authors: Singh Ankita , Adam Awadalkareem , Aditi  , Peng Bi-Hung , Yu Xiaoying , Zou Jing , Kulkarni Vikram V , Kan Peter , Jiang Wei , Shi Pei-Yong , Samir Parimal , Cisneros Irma , Wang Tian 
Published: January 2024

ABSTRACTViral variant is one known risk factor associated with post-acute sequelae of COVID-19 (PASC), yet the pathogenesis is largely unknown. Here, we studied SARS-CoV-2 Delta variant-induced PASC in K18-hACE2 mice. The virus replicated productively, induced robust inflammatory responses in lung and brain tissues, and caused weight loss and mortality during the acute infection. Longitudinal behavior studies in surviving mice up to 4 months post-acute infection revealed persistent abnormalities in neuropsychiatric state and motor behaviors, while reflex and sensory functions recovered over time. Surviving mice showed no detectable viral RNA in the brain and minimal neuroinflammation post-acute infection. Transcriptome analysis revealed persistent activation of immune pathways, including humoral responses, complement, and phagocytosis, and reduced levels of genes associated with ataxia telangiectasia, impaired cognitive function and memory recall, and neuronal dysfunction and degeneration. Furthermore, surviving mice maintained potent T helper 1 prone cellular immune responses and high neutralizing antibodies against Delta and Omicron variants in the periphery for months post-acute infection. Overall, infection in K18-hACE2 mice recapitulates the persistent clinical symptoms reported in long COVID patients and may be useful for future assessment of the efficacy of vaccines and therapeutics against SARS-CoV-2 variants.
Somatic cancer driver mutations are enriched and associated with inflammatory states in Alzheimer’s disease microglia
Authors: Huang August Yue , Zhou Zinan , Talukdar Maya , Miller Michael B. , Chhouk Brian , Enyenihi Liz , Rosen Ila , Stronge Edward , Zhao Boxun , Kim Dachan , Choi Jaejoon , Khoshkhoo Sattar , Kim Junho , Ganz Javier , Travaglini Kyle , Gabitto Mariano , Hodge Rebecca , Kaplan Eitan , Lein Ed , De Jager Philip L. , Bennett David A. , Lee Eunjung Alice , Walsh Christopher A. 
Published: January 2024

SummaryAlzheimer’s disease (AD) is an age-associated neurodegenerative disorder characterized by progressive neuronal loss and pathological accumulation of the misfolded proteins amyloid-β and tau1,2. Neuroinflammation mediated by microglia and brain-resident macrophages plays a crucial role in AD pathogenesis1–5, though the mechanisms by which age, genes, and other risk factors interact remain largely unknown. Somatic mutations accumulate with age and lead to clonal expansion of many cell types, contributing to cancer and many non-cancer diseases6,7. Here we studied somatic mutation in normal aged and AD brains by three orthogonal methods and in three independent AD cohorts. Analysis of bulk RNA sequencing data from 866 samples from different brain regions revealed significantly higher (∼two-fold) overall burdens of somatic single-nucleotide variants (sSNVs) in AD brains compared to age-matched controls. Molecular-barcoded deep (>1000X) gene panel sequencing of 311 prefrontal cortex samples showed enrichment of sSNVs and somatic insertions and deletions (sIndels) in cancer driver genes in AD brain compared to control, with recurrent, and often multiple, mutations in genes implicated in clonal hematopoiesis (CH)8,9. Pathogenic sSNVs were enriched in CSF1R+ microglia of AD brains, and the high proportion of microglia (up to 40%) carrying some sSNVs in cancer driver genes suggests mutation-driven microglial clonal expansion (MiCE). Analysis of single-nucleus RNA sequencing (snRNAseq) from temporal neocortex of 62 additional AD cases and controls exhibited nominally increased mosaic chromosomal alterations (mCAs) associated with CH10,11. Microglia carrying mCA showed upregulated pro-inflammatory genes, resembling the transcriptomic features of disease-associated microglia (DAM) in AD. Our results suggest that somatic driver mutations in microglia are common with normal aging but further enriched in AD brain, driving MiCE with inflammatory and DAM signatures. Our findings provide the first insights into microglial clonal dynamics in AD and identify potential new approaches to AD diagnosis and therapy.
Loss of αBa-crystallin, but not αA-crystallin, increases age-related cataract in the zebrafish lens
Authors: Posner Mason , Garver Taylor , Kaye Taylor , Brdicka Stuart , Suttle Madison , Patterson Bryce , Farnsworth Dylan R. 
Published: January 2024

AbstractThe vertebrate eye lens is an unusual organ in that most of its cells lack nuclei and the ability to replace aging protein. The small heat shock protein α-crystallins evolved to become key components of this lens, possibly because of their ability to prevent aggregation of aging protein that would otherwise lead to lens opacity. Most vertebrates express two α-crystallins, αA- and αB-crystallin, and mutations in each are linked to human cataract. In a mouse knockout model only the loss of αA-crystallin led to early-stage lens cataract. We have used the zebrafish as a model system to investigate the role of α-crystallins during lens development. Interestingly, while zebrafish express one lens-specific αA-crystallin gene (cryaa), they express two αB-crystallin genes, with one evolving lens specificity (cryaba) and the other retaining the broad expression of its mammalian ortholog (cryabb). In this study we used individual mutant zebrafish lines for all three α-crystallin genes to determine the impact of their loss on age-related cataract. Surprisingly, unlike mouse knockout models, we found that the loss of the αBa-crystallin genecryabaled to an increase in lens opacity compared tocryaanull fish at 24 months of age. Loss of αA-crystallin did not increase the prevalence of cataract. We also used single cell RNA-Seq and RT-qPCR data to show a shift in the lens expression of zebrafish α-crystallins between 5 and 10 days post fertilization (dpf), with 5 and 6 dpf lenses expressingcryaaalmost exclusively, and expression ofcryabaandcryabbbecoming more prominent after 10 dpf. These data show thatcryaais the primary α-crystallin during early lens development, while the protective role forcryababecomes more important during lens aging. This study is the first to quantify cataract prevalence in wild-type zebrafish, showing that lens opacities develop in approximately 25% of fish by 18 months of age. None of the three α-crystallin mutants showed a compensatory increase in the expression of the remaining two crystallins, or in the abundant βB1-crystallin. Overall, these findings indicate an ontogenetic shift in the functional importance of individual α-crystallins during zebrafish lens development. Our finding that the lens-specific zebrafish αBa-crystallin plays the leading role in preventing age-related cataract adds a new twist to our understanding of vertebrate lens evolution.