bluuebunny/crossref_metadata_2025_split huggingface dataset:
Park7deletion leads to age- and sex-specific transcriptome changes involving NRF2-CYP1B1 axis in mouse midbrain astrocytes
Authors: Helgueta Sergio , Heurtaux Tony , Sciortino Alessia , Gui Yujuan , Ohnmacht Jochen , Mencke Pauline , Boussaad Ibrahim , Halder Rashi , Garcia Pierre , Krüger Rejko , Mittelbronn Michel , Buttini Manuel , Sauter Thomas , Sinkkonen Lasse 
Published: February 2024

AbstractdispeLoss-of-function mutations inPARK7, encoding for DJ-1, can lead to early onset Parkinson’s disease (PD). In mice,Park7deletion leads to dopaminergic deficits during aging, and increased sensitivity to oxidative stress. However, the severity of the reported phenotypes varies. To understand the early molecular changes upon loss of DJ-1, we performed transcriptomic profiling of midbrain sections from young mice. Interestingly, while at 3 months the transcriptomes of both male and female mice were unchanged compared to their wildtype littermates, an extensive deregulation was observed specifically in 8-month-old males. The affected genes are involved in processes such as focal adhesion, extracellular matrix interaction, and epithelial-to-mesenchymal transition (EMT), and enriched for primary target genes of Nuclear factor erythroid 2-related factor 2 (NRF2). Consistently, the antioxidant response was altered specifically in the midbrain of male DJ-1 deficient mice. Many of the misregulated genes are known target genes of estrogen and retinoic acid signaling and show sex-specific expression in wildtype mice. Depletion of DJ-1 or NRF2 in male, but not female primary astrocytes recapitulated many of thein vivochanges, including downregulation of cytochrome P450 family 1 subfamily B member 1 (CYP1B1), an enzyme involved in estrogen and retinoic acid metabolism. Interestingly, knock-down of CYP1B1 led to gene expression changes in focal adhesion and EMT in primary male astrocytes. Finally, male iPSC-derived astrocytes with loss of function mutation in thePARK7gene also showed changes in the EMT pathway and NRF2 target genes. Taken together, our data indicate that loss ofPark7leads to sex-specific gene expression changes specifically in males through astrocytic alterations in the NRF2-CYP1B1 axis. These findings suggest higher sensitivity of males to loss of DJ-1 and might help to better understand variation in the reportedPark7−/−phenotypes.
Gene Expression Reactomes Across Species Do Not Correlate with Gene Structural Similarity
Authors: Chen Wei , Chai Yi , Cui Nancy Y. , Gopinath Ashwin , Zhang David Yu 
Published: February 2024

AbstractMammalian animal model species for preclinical drug testing share a large number of genes with similar names and/or protein primary structures, but gene expression patterns in different tissues and in response to different drugs have not been previously systematically characterized. Here, we experimentally measure the gene expression responses (reactomes) of each gene in the mouse and rat genomes in 10 different organs to 3 different drugs. Surprisingly, we observe that gene reactomes across species generally do not correlate with structural similarity. Thus, we propose an alternative functional cross-species gene mapping approach, based on organ-specific gene expression response to drug dosing.
BET Degraders Reveal BRD4 Disruption of 7SK and P-TEFb is Critical for Effective Reactivation of Latent HIV in CD4+ T-cells
Authors: Turner Anne-Marie W. , Bashore Frances M. , Falcinelli Shane D. , Fox Joshua A. , Keller Alana L. , Fenton Anthony D. , Geyer Renee F. , Allard Brigitte , Kirchherr Jennifer L. , Archin Nancie M. , James Lindsey I. , Margolis David M. 
Published: February 2024

AbstractHIV cure strategies that aim to induce viral reactivation for immune clearance leverage latency reversal agents to modulate host pathways which directly or indirectly facilitate viral reactivation. Inhibition of BET (bromo and extra-terminal domain) family member BRD4 reverses HIV latency, but enthusiasm for the use of BET inhibitors in HIV cure studies is tempered by concerns over inhibition of other BET family members and dose-limiting toxicities in oncology trials. Here we evaluated the potential for bivalent chemical degraders targeted to the BET family as alternative latency reversal agents. We observed that despite highly potent and selective BRD4 degradation in primary CD4+ T-cells from ART-suppressed donors, BRD4 degraders failed to induce latency reversal as compared to BET inhibitors. Further, BRD4 degraders failed to mimic previously observed synergistic HIV reactivation between BET inhibitors and an activator of the non-canonical NF-κB pathway. Mechanistic investigation of this discrepancy revealed that latency reversal by BET inhibitors is not related to the abatement of competition between Tat and BRD4 for P-TEFb, but rather the ability of BRD4 to disrupt 7SK and increase the levels of free P-TEFb. This activity is dependent on the shift of BRD4 from chromatin-bound to soluble and retargeting of P-TEFb to chromatin which is dependent on intact BRD4 but independent of the bromodomains.
An uncommon phosphorylation mode regulates the activity and protein-interactions of N-acetylglucosamine kinase
Authors: Celik Arif , Beyer Ida , Fiedler Dorothea 
Published: February 2024

AbstractWhile the function of protein phosphorylation in eukaryotic cell signaling is well established, the role of a closely related modification, protein pyrophosphorylation, is just starting to surface. A recent study has identified several targets of endogenous protein pyrophosphorylation in mammalian cell lines, including N-acetylglucosamine kinase (NAGK). Here, a detailed functional analysis of NAGK phosphorylation and pyrophosphorylation on serine 76 (S76) has been conducted. This analysis was enabled by using amber codon suppression to obtain phosphorylated pS76-NAGK, which was subsequently converted to site-specifically pyrophosphorylated NAGK (ppS76-NAGK) with a phosphorimidazolide regent. A significant reduction in GlcNAc kinase activity was observed upon phosphorylation, and near-complete inactivation upon pyrophosphorylation. The formation of ppS76-NAGK proceededviaan ATP-dependent autocatalytic process, and once formed, ppS76-NAGK displayed notable stability towards dephosphorylation in mammalian cell lysates. Proteomic examination unveiled a distinct set of protein-protein interactions for ppS76-NAGK, suggesting an alternative function, independent of its kinase activity. Overall, a significant regulatory role of pyrophosphorylation on NAGK activity was uncovered, providing a strong incentive to investigate the influence of this unusual phosphorylation mode on other kinases.
Epigenetic Control of Adaptive or Homeostatic Splicing of Alternative Exons andProlactinGene Expression During Interval-Training Activities of Pituitary Cells
Authors: Liu Ling , Nguyen Hai , Das Urmi , Ogunsola Samuel , Yu Jiankun , Lei Lei , Kung Matthew , Pejhan Shervin , Rastegar Mojgan , Xie Jiuyong 
Published: February 2024

AbstractInterval-training activities induce adaptive cellular changes without altering their fundamental identity, but the precise underlying molecular mechanisms are not fully understood. In this study, we demonstrate that interval-training depolarization (ITD) of pituitary cells triggers distinct adaptive or homeostatic splicing responses of alternative exons. This occurs while preserving the steady-state expression of theProlactinand other hormone genes. The nature of these splicing responses depends on the exon’s DNA methylation status, the methyl-C-binding protein MeCP2 and its associated CA-rich motif-binding hnRNP L. Interestingly, the steady expression of theProlactingene is also reliant on MeCP2, whose disruption during ITD leads to exacerbated overexpression and multi-exon aberrant splicing of the hormone gene transcripts, similar to the observed hyperprolactinemia or activity-dependent aberrant splicing in Rett Syndrome. Therefore, depending on how many times cells are stimulated, exons may exhibit different splicing responses to cell activities. During the ITD, epigenetic control is crucial for both adaptive or homeostatic splicing and the steady expression of theProlactinhormone gene. Disruption in this regulation may have significant implications for the development of progressive diseases.
Asynchronous abundance fluctuations can drive giant genotype frequency fluctuations
Authors: Ascensao Joao A , Lok Kristen , Hallatschek Oskar 
Published: February 2024

ABSTRACTLarge stochastic population abundance fluctuations are ubiquitous across the tree of life1–7, impacting the predictability of population dynamics and influencing eco-evolutionary outcomes. It has generally been thought that these large abundance fluctuations do not strongly impact evolution, as the relative frequencies of alleles in the population will be unaffected if the abundance of all alleles fluctuate in unison. However, we argue that large abundance fluctuations can lead to significant genotype frequency fluctuations if different genotypes within a population experience these fluctuations asynchronously. By serially diluting mixtures of two closely relatedE. colistrains, we show that such asynchrony can occur, leading to giant frequency fluctuations that far exceed expectations from models of genetic drift. We develop a flexible, effective model that explains the abundance fluctuations as arising from correlated offspring numbers between individuals, and the large frequency fluctuations result from even slight decoupling in offspring numbers between genotypes. This model accurately describes the observed abundance and frequency fluctuation scaling behaviors. Our findings suggest chaotic dynamics underpin these giant fluctuations, causing initially similar trajectories to diverge exponentially; subtle environmental changes can be magnified, leading to batch correlations in identical growth conditions. Furthermore, we present evidence that such decoupling noise is also present in mixed-genotypeS. cerevisiaepopulations. We demonstrate that such decoupling noise can strongly influence evolutionary outcomes, in a manner distinct from genetic drift. Given the generic nature of asynchronous fluctuations, we anticipate that they are widespread in biological populations, significantly affecting evolutionary and ecological dynamics.
New Dual Inducible Cellular Model to Investigate Temporal Control of Oncogenic Cooperating Genes
Authors: Kent Matthew R. , Jay Amanda N. , Kendall Genevieve C. 
Published: February 2024

AbstractThe study of cooperating genes in cancer can lead to mechanistic understanding and identifying potential therapeutic targets. To facilitate these types of studies, we developed a new dual-inducible system utilizing the tetracycline- and cumate-inducible systems driving HES3 and the PAX3::FOXO1 fusion-oncogene, respectively, as cooperating genes from fusion-positive rhabdomyosarcoma. With this new model, we can independently induce expression of either HES3 or PAX3::FOXO1, as well as simultaneously induce expression of both genes. This new model will allow us to further investigate the cooperation between HES3 and PAX3::FOXO1 including the temporal requirements for genetic cooperation. This dual-inducible model can be adapted for any cooperating genes, allowing for independent, simultaneous, or temporally controlled gene expression.
CACTI: An in-silicodrug-target prediction tool through the integration of chemogenomic data and clustering analysis
Authors: Godinez-Macias Karla P. , Winzeler Elizabeth A. 
Published: February 2024

AbstractIt is well-accepted that knowledge of a small molecule’s target can accelerate optimization. Although chemogenomic databases are helpful resources for predicting or finding compound interaction partners, they tend to be limited and poorly annotated. Furthermore, unlike genes, compound identifiers are often not standardized, and many synonyms may exist, especially in the biological literature, making batch analysis of compounds difficult. Here, we constructed an open-source annotation and target prediction tool that explores some of the largest chemical and biological databases, mining these for both common name, synonyms, and structurally similar molecules. We used this Chemical Analysis and Clustering for Target Identification (CACTI) tool to analyze the Pathogen Box collection, an open-source set of 400 drug-like compounds active against a variety of microbial pathogens. Our analysis resulted in 4,315 new synonyms, 35,963 pieces of new information and target prediction hints for 58 members.Scientific ContributionWith the employment of this tool, a comprehensive report with known evidence, close analogs and drug-target prediction can be obtained for large-scale chemical libraries that will facilitate their evaluation and future target validation and optimization efforts.
Topographical changes in extracellular matrix during skin fibrosis and recovery can be evaluated using automated image analysis algorithms
Authors: Wyetzner Rachel H. , Segal Ella X. , Jussila Anna R. , Atit Radhika P. 
Published: February 2024

AbstractSkin fibrosis is characterized by fibroblast activation and intradermal fat loss, resulting in excess deposition and remodeling of dermal extracellular matrix (ECM). The topography of the dominant ECM proteins, such as collagens, can indicate skin stiffness and remains understudied in evaluating fibrotic skin. Here, we adapted two different unbiased image analysis algorithms to define collagen topography and alignment in a genetically inducible and reversible Wnt activation fibrosis model. We demonstrated that Wnt activated fibrotic skin has altered collagen fiber characteristics and a loss of collagen alignment, which were restored in the reversible model. This study highlights how unbiased algorithms can be used to analyze ECM topography, providing novel avenues to evaluate fibrotic skin onset, recovery, and treatment.
KSR1 mediates small-cell lung carcinoma tumor initiation and cisplatin resistance
Authors: Chatterjee Deepan , Svoboda Robert A. , Huisman Dianna H. , Drapkin Benjamin J , Vieira Heidi M. , Rao Chaitra , Askew James W. , Fisher Kurt W. , Lewis Robert E. 
Published: February 2024

AbstractSmall-cell lung cancer (SCLC) has a dismal five-year survival rate of less than 7%, with limited advances in first line treatment over the past four decades. Tumor-initiating cells (TICs) contribute to resistance and relapse, a major impediment to SCLC treatment. Here, we identify Kinase Suppressor of Ras 1 (KSR1), a molecular scaffold for the Raf/MEK/ERK signaling cascade, as a critical regulator of SCLC TIC formation and tumor initiationin vivo. We further show that KSR1 mediates cisplatin resistance in SCLC. While 50-70% of control cells show resistance after 6-week exposure to cisplatin, CRISPR/Cas9-mediated KSR1 knockout prevents resistance in >90% of SCLC cells in ASCL1, NeuroD1, and POU2F3 subtypes. KSR1 KO significantly enhances the ability of cisplatin to decrease SCLC TICs viain vitroextreme limiting dilution analysis (ELDA), indicating that KSR1 disruption enhances the cisplatin toxicity of cells responsible for therapeutic resistance and tumor initiation. The ability of KSR1 disruption to prevent cisplatin resistant in H82 tumor xenograft formation supports this conclusion. Previous studies indicate that ERK activation inhibits SCLC tumor growth and development. We observe a minimal effect of pharmacological ERK inhibition on cisplatin resistance and no impact on TIC formation viain vitroELDA. However, mutational analysis of the KSR1 DEF domain, which mediates interaction with ERK, suggests that ERK interaction with KSR1 is essential for KSR1-driven cisplatin resistance. These findings reveal KSR1 as a key regulatory protein in SCLC biology and a potential therapeutic target across multiple SCLC subtypes.Statement of ImplicationGenetic manipulation of the molecular scaffold KSR1 in small-cell lung cancer cells reveals its contribution to cisplatin resistance and tumor initiation.
GhCPK28 negatively regulates the immune response by phosphorylating GhTIFY3b
Authors: Gao Shengqi , Shao Wukui , Wu Jiawen , Zhao Zhun , Hu Wenran , Shao Panxia , Hua Jian , Zou Baohong , Huang Quansheng 
Published: February 2024

AbstractThe soil-borne fungusVerticillium dahliae(V. dahliae) seriously inhibits cotton (Gossypium hirsutum) growth and productivity. The immune system of cotton against this pathogen is largely unknown. Here we investigated the involvement of Ca2+-dependent protein kinases (CPKs) in this immunity. One CPK coding geneGhCPK28had reduced expression after infection byV. dahliaein cotton. Knocking down of theGhCPK28by virus induced gene silencing led to enhanced resistance toV. dahliaewhich is accompanied by a higher ROS accumulation and systemic acquired response. GhCPK28 was found to phosphorylate a TIFY family protein GhTIFY3b and reduce its stability. SilencingGhTIFY3bincreased the susceptibility of cotton toV. dahliae. Together, this study indicate that GhCPK28 is a negative regulator of defense againstV. dahliaeinfection and the GhTIFY3b might be a target protein of its activity. It sheds light on the immune system againstV. dahliaeand provides candidate genes for improving resistance against Verticillium wilt in cotton.
PRENATAL STRESS MODIFIES SPATIAL COGNITION IN MICE: EFFECTS OF AGE AND SEX
Authors: McCarthy M , Buck TG , Sodhi MS 
Published: February 2024

AbstractPrenatal stress is linked with neuropathology of the cortical-hippocampal circuit, due to abnormal brain development that leads to long term neurological deficits in offspring, in both rodents and in humans with psychiatric disorders. Conflicting reports exist of the effects of prenatal stress in C57BL/6J mice, which is an inbred strain that is the most frequently used for neurobehavioral research. We now present comprehensive analyses of the effects of prenatal stress on spatial cognition and related behaviors in this inbred strain, in males and females at young adult and aged adult stages. The prenatal stress exposure was conducted by exposing pregnant mice to restraint stress three times daily from day 7 to day 18 of gestation. We tested the effects of prenatal stress on cognitive behavior using a battery of behavioral assays including the open-field test, the light-dark box, Morris water maze spatial acquisition and spatial reversal testing, in addition to assays of social interaction and social memory. We compared the behavioral phenotype of male and female offspring in young adult (10-20 weeks) and older adult ages (60- 70 weeks). Data reveal that male but not female mice had reduced body weight throughout the lifespan after exposure to prenatal stress. Young prenatally stressed adult females showed greater organization of tracking behavior in spatial acquisition tests than other groups. Prenatal stress improved reversal learning in aged females relative to non-stressed aged females. We detected decreased extinction of the spatial acquisition memory in prenatally stressed young adult mice of both sexes. Overall results indicate that prenatal stress may protect females from detrimental effects of age on function of the hippocampus. Our data support the finding that C57BL/6J are a relatively resilient strain of mouse that may be useful for investigating the differences between resilience and susceptibility to stress. Genomic differences between the C57BL/6J strain relative to Swiss Webster strain, which is more susceptible to prenatal stress are discussed. Future studies of prenatal stress in the C57BL/6J mouse strain should focus on the identification of molecular pathways that underlie resilience to prenatal stress, to identify novel targets for drug development.
Synthetic type III-E CRISPR-Cas effectors for programmable RNA-targeting
Authors: Brogan Daniel J. , Benetta Elena Dalla , Wang Tianqi , Lin Calvin P. , Chen Fangying , Li Harry , Lin Claire , Komives Elizabeth A. , Akbari Omar S. 
Published: February 2024

AbstractThe recent discovery of the type III-E CRISPR-Cas effector class has reshaped our fundamental understanding of CRISPR-Cas evolution and classification. Type III-E effectors are composed of several Cas7-like domains and a single Cas11-like domain naturally fused together to create a single polypeptide capable of programmably targeting and degrading RNA. Here we identify a novel composition of a type III-E-like effector composed of Cas7-like and a Cas1-like domain, that can be engineered into an active chimeric RNA-targeting Cas effector and presents a new function of Cas1 in RNA-targeting. Furthermore, we demonstrate a unique modularity of type III-E effectors by methodically substituting domains between orthogonal type III-E proteins to engineer compact synthetic Cas effectors. We refine our methods to generate several compact effectors for programmable RNA-targeting in mammalian cells. Cas7-S represents a new understanding of type III-E architecture and modularity, and provides a platform for engineering genome engineering technologies from the blueprint of nature.
Exploring the repository ofde novodesigned bifunctional antimicrobial peptides through deep learning
Authors: Dong Ruihan , Liu Rongrong , Liu Ziyu , Liu Yangang , Zhao Gaomei , Li Honglei , Hou Shiyuan , Ma Xiaohan , Kang Huarui , Liu Jing , Guo Fei , Zhao Ping , Wang Junping , Wang Cheng , Wu Xingan , Ye Sheng , Zhu Cheng 
Published: February 2024

AbstractAntimicrobial peptides (AMPs) are attractive candidates to combat antibiotic resistance for their capability to target bio-membranes and restrict a wide range of pathogens. It is a daunting challenge to discover novel AMPs due to their sparse distributions in a vast peptide universe, especially for peptides that demonstrate potencies for both bacterial membranes and viral envelopes. Here we establish ade novoAMP design framework by bridging a deep generative module and a graph-encoding activity regressor. The generative module learns hidden ‘grammars’ of AMP features and produces candidates sequentially pass antimicrobial predictor and antiviral classifiers. We discover 16 bifunctional AMPs and experimentally validated their abilities to inhibit a spectrum of pathogensin vitroand in animal models. Notably, P076 is a highly potent bactericide with the minimal inhibitory concentration of 0.21 μM against multidrug-resistantA. baumannii, while P002 broadly inhibits five enveloped viruses. Our study provides feasible means to uncover sequences that simultaneously encode antimicrobial and antiviral activities, thus bolstering the function spectra of AMPs to combat a wide range of drug-resistant infections.
Deep Learning Behavioral Phenotyping System in the Diagnosis of Parkinson’s Disease with Drosophila melanogaster
Authors: Dong Keyi , Burch April , Huang Kang 
Published: February 2024

AbstractDrosophila Melanogasteris widely used as animal models for Parkinson’s disease (PD) research. Because of the complexity of MoCap and quantitative assessment amongDrosophila Melanogaster, however, there is a technical issue that identify PD symptoms within drosophila based on objective spontaneous behavioral characteristics. Here, we developed a deep learning framework generated from kinematic features of body posture and motion between wildtype and SNCAE46Kmutant drosophila genetically modeled □-Syn, supporting clustering and classification of PD individuals. We record locomotor activity in a 3D-printed trap, and utilize the pre-analysis pose estimation software DeepLabCut (DLC) to calculate and generate numerical data representing the motion speed, tremor frequency, and limb motion ofDrosophila Melanogaster. By plugging these data as the input, the diagnosis result (1/0) representing PD or WT as the output. Our result provides a toolbox which would be valuable in the investigation of PD progressing and pharmacotherapeutic drug development.