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Variations in kinase and effector signaling logic in a bacterial two component signaling network

Journal of Biological Chemistry 2025年第6期301卷 108534页

作者： Swingle, Danielle Epstein, Leah Aymon, Ramisha Isiorho, Eta A. Abzalimov, Rinat R. Favaro, Denize C. Gardner, Kevin H. Structural Biology Initiative CUNY Advanced Science Research Center New YorkNY United States PhD. Program in Biochemistry The Graduate Center – City University of New York New YorkNY United States Department of Chemistry and Biochemistry City College of New York New YorkNY United States PhD. Programs in Biochemistry Biology and Chemistry The Graduate Center – City University of New York New YorkNY United States

The general stress response (GSR) protects bacteria from a wide range of stressors. In Alphaproteobacteria, GSR activation is coordinated by HWE/HisKA2 family histidine kinases (HKs), which can exhibit noncanonical structure and function. For example, while most light-oxygen-voltage sensor-containing HKs are light-activated dimers, the Rubellimicrobium thermophilum RT-HK has inverted "dark on, light off" signaling logic with a tunable monomer/dimer equilibrium. Here, we further investigate these atypical behaviors of RT-HK and characterize its downstream signaling network. Using hydrogen-deuterium exchange mass spectrometry, we find that RT-HK uses a signal transduction mechanism similar to light-activated systems, despite its inverted logic. Mutagenesis reveals that RT-HK autophosphorylates in trans, with changes to the Jα helix linking sensor and kinase domains affecting autophosphorylation levels. Exploring downstream effects of RT-HK, we identified two GSR genetic regions, each encoding a copy of the central regulator PhyR. In vitro measurements of phosphotransfer from RT-HK to the two putative PhyRs revealed that RT-HK signals only to one and does so at an increased intensity in the dark, consistent with its reversed logic. X-ray crystal structures of both PhyRs revealed a substantial shift within the receiver domain of one, suggesting a basis for RT-HK specificity. We probed further down the pathway using nuclear magnetic resonance to determine that the single NepR homolog interacts with both unphosphorylated PhyRs, and this interaction is decoupled from activation in one PhyR. This work expands our understanding of HWE/HisKA2 family signal transduction, revealing marked variations from signaling mechanisms previously identified in other GSR networks. © 2025 The Authors

关键词： Signaling

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DNA-damage-associated protein co-expression network in cardiomyocytes informs on tolerance to genetic variation and disease

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iScience 2025年第5期28卷

作者： Johnson, Omar Darrel Paul, Sayan Gutiérrez, José Angel Russell, William Kent Ward, Michelle Claire Biochemistry Cellular and Molecular Biology Graduate Program University of Texas Medical Branch Galveston 77555 TX United States MD-PhD Combined Degree Program University of Texas Medical Branch Galveston 77555 TX United States Department of Biochemistry and Molecular Biology University of Texas Medical Branch Galveston 77555 TX United States

Cardiovascular disease (CVD) is associated with genetic variants and environmental factors. A consequence of multiple risk factors is DNA damage. To examine how DNA damage influences the cardiomyocyte proteome and its relationship to CVD risk, we treated human induced pluripotent stem cell (iPSC)-derived cardiomyocytes with the DNA-damaging agent doxorubicin (DOX). A network constructed from 4,178 proteins reveals 12 co-expressed modules with 403 hub proteins. Five modules correlate with DOX and associate with RNA processing, chromatin regulation, and metabolism. DOX-correlated hub proteins are depleted for proteins that vary in expression across individuals due to genetic variation but are enriched for proteins encoded by loss-of-function intolerant genes. While not enriched for known CVD risk proteins, DOX-correlated hub proteins are enriched for the physical protein interactors of CVD risk proteins. These data demonstrate that protein connectivity in DNA-damage-associated modules influences the tolerance to genetic variation and supports the use of dynamic networks to explore complex traits. © 2025 The Author(s)

关键词： Integrative aspects of cell biology Molecular network Proteomics

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Directed discovery of high-loading nanoaggregates enabled by drug-matched oligo-peptide excipients

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Chem 2025年

作者： Berisha, Naxhije Farahpour, Atena Ramakrishnan, Maithreyi Chen, Chen McPhee, Scott A. Wang, Tong Li, Tai-De Hema, Kuntrapakam Panagiotakopoulou, Magdalini Athiyarath, Vignesh Coste, Maeva Marciano, Yaron Sherman, Emmet Ulijn, Rein V. Heller, Daniel A. Nanoscience Initiative Advanced Science Research Center CUNY Graduate Center City University of New York New York 10031 NY United States Department of Chemistry and Biochemistry Hunter College City University of New York New York 10065 NY United States PhD Program in Chemistry CUNY Graduate Center City University of New York New York 10016 NY United States Molecular Pharmacology Program Memorial Sloan Kettering Cancer Center New York 10065 NY United States Tri-Institutional PhD Program in Chemical Biology Memorial Sloan Kettering Cancer Center New York 10065 NY United States Department of Physics City College of New York City University of New York New York 10031 NY United States Department of Chemistry Brooklyn College City University of New York 2900 Bedford Avenue Brooklyn 11210 NY United States PhD Program in Biochemistry CUNY Graduate Center City University of New York New York 10016 NY United States Weill Cornell Medicine Cornell University New York 10065 NY United States

Nanoparticles can improve drug pharmacokinetics, but low loading efficiencies can limit treatment efficacy. Drug-aggregation-based nanoparticles have demonstrated improved loadings of up to 90%, but few excipients facilitate efficient co-assembly. We investigated peptides as designer excipients because of their diverse chemical space and inherent biodegradability. We designed pentapeptide scaffolds to mimic the structure of known indocyanine excipients by modulating aromaticity, rigidity, and charge. We screened 184 formulations by using diverse drug cargoes. We found drug-peptide combinations that formed nanoparticles with up to 98% drug loading. Molecular dynamics simulations and mass spectrometry analysis demonstrated that tryptophan-drug interactions and solvent exposure of charged amino acid residues drove the formation of core-shell structures. Peptide-drug formulations containing the JAK2/FLT3 inhibitor lestaurtinib were investigated in acute myeloid leukemia models, resulting in enhanced anti-tumor efficacy. This work found that oligopeptides can be designed to efficiently co-assemble with therapeutic cargoes to result in high-loading nanoparticles that improve anti-tumor efficacy. © 2024

关键词： co-assembly directed discovery drug delivery excipient nanocarrier design nanoparticle oligopeptides SDG3: Good health and well-being

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BPS2025 - Analysis of the steady states of systems of dynamic microtubules: Polymer length distribution steady state

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Biophysical Journal 2025年第3期124卷 139a-139a页

作者： Alexander W. Simmons Sayandeepa Raha Theodore N. Berente Holly V. Goodson Department of Chemistry and Biochemistry University of Notre Dame Notre Dame IN USA Biophysics PhD Program University of Notre Dame Notre Dame IN USA Integrated Biomedical Sciences PhD Program University of Notre Dame Notre Dame IN USA QuarkNet University of Notre Dame Notre Dame IN USA St. Joseph High School South Bend IN USA

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SKA2/FAM33A:A novel gene implicated in cell cycle,tumorigenesis,and psychiatric disorders

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Genes & Diseases 2019年第1期6卷 25-30页

作者： Mengyu Xie Youquan Bu Department of Biochemistry and Molecular Biology College of Basic Medical SciencesChongQing Medical UniversityChongqing400016China Cancer Biology PhD Program University of South FloridaTampaFL33612USA

SKA2(spindle and KT associated 2),also referred to as FAM33A(family with sequence similarity 33,member A),is a recently identified gene involved in cell cycle regulation,and growing evidence is implicating its roles in tumorigenesis and psychiatric *** has been demonstrated that SKA2,along with its coworkers SKA1 and SKA3,constitutes the SKA complex which plays a critical role in the maintenance of the metaphase plate and/or spindle checkpoint silencing during ***2 is over-expressed both in cancer cell lines and clinical samples including small cell lung cancer and breast cancer,whereas downregulation of SKA2 is associated with depression and suicidal *** expression of SKA2 is regulated by transcription factors including NF-kB and CREB,miRNAs as well as DNA *** this review,we provide an overview of studies that reveal SKA2 gene and protein characteristics as well as physiological function,with a special focus on its transcription regulatory mechanisms,and also provide a summary regarding the translational opportunity of the SKA2 gene as a clinical biomarker for cancers and psychiatric disorders.

关键词： SKA2 FAM33A Cell cycle Tumor Gene expression regulation DNA methylation

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Animal Models of Malaria-Associated Acute Kidney Injury

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Seminars in Nephrology 2025年 151616页

作者： Mamudu, Collins Ojonugwa Polidoro, Rafael Gallego-Delgado, Julio Department of Biological Sciences Lehman College City University of New York Bronx New York NY United States PhD Program in Biochemistry The Graduate Center City University of New York New York NY United States Department of Pediatrics Ryan White Center for Pediatric Infectious Diseases and Global Health Herman B Wells Center for Pediatric Research Indiana University School of Medicine Indianapolis IN United States PhD Program in Biology The Graduate Center City University of New York New York NY United States

Malaria-associated acute kidney injury (MAKI) is a critical complication of severe malaria, particularly in infections caused by Plasmodium falciparum, which is responsible for most malaria-related deaths. MAKI affects 40-60% ofs severe malaria cases, significantly increasing mortality, especially in pediatric patients. Its pathogenesis remains unclear, though mechanisms such as hemodynamic disturbances, oxidative stress, and immune responses are implicated. Animal models, particularly murine and nonhuman primates, provide valuable insights into MAKI's underlying processes. Murine models, though not fully replicative of human malaria, allow for the exploration of immune responses, kidney injury biomarkers, and therapeutic approaches. Nonhuman primate models, closer to human physiology, offer additional complexity for studying malaria's renal manifestations. This review critically examines the existing animal models, addressing their strengths and limitations in replicating human MAKI and highlighting the importance of advancing research in this field to develop targeted treatments. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved. © 2025

关键词： acute kidney injury Malaria malaria animal models murine nonhuman primate

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Teaching Green Chemistry Through Student-Generated Open Educational Resources

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Journal of College Science Teaching 2023年第4期52卷 3-5页

作者： Grieger, Krystal Leontyev, Alexey Department of Chemistry and Biochemistry North Dakota State University in Fargo ND United States Department of Chemistry and Biochemistry and Discipline-Based Education Research PhD Program North Dakota State University Fargo ND United States

This article describes the implementation of a student-generated open educational resource project into a majors ’ organic chemistry laboratory. This scaffolded semester-long project was organized into six phases and designed to promote the goals of teaching students about both green chemistry and real-life applications of the reactions covered in the course while simultaneously creating open educational resources for future students. A project-based learning approach was utilized to promote student engagement, especially during remote instruction. To further promote engagement, multiple opportunities for peer feedback were provided using web-based software that supports anonymous feedback. The effect of the project on cognitive learning gains and student perceptions was assessed and is reported. Overall, positive learning gains on green chemistry knowledge and skills were observed, and most students viewed the project favorably. © 2023 National Science Teaching Association.

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An atlas of single-cell eQTLs dissects autoimmune disease genes and identifies novel drug classes for treatment

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Cell Genomics 2025年第4期5卷 100820-100820页

作者： Wang, Lida Markus, Havell Chen, Dieyi Chen, Siyuan Zhang, Fan Gao, Shuang Khunsriraksakul, Chachrit Chen, Fang Olsen, Nancy Foulke, Galen Jiang, Bibo Carrel, Laura Liu, Dajiang J. Department of Public Health Sciences Pennsylvania State University College of Medicine Hershey 17033 PA United States Bioinformatics and Genomics PhD Program Pennsylvania State University College of Medicine Hershey 17033 PA United States Institute for Personalized Medicine Pennsylvania State University College of Medicine Hershey 17033 PA United States Department of Biochemistry and Molecular Biology Pennsylvania State University College of Medicine Hershey 17033 PA United States Department of Medicine Penn State University College of Medicine Hershey 17033 PA United States Department of Dermatology Penn State University College of Medicine Hershey 17033 PA United States

Most variants identified from genome-wide association studies (GWASs) are non-coding and regulate gene expression. However, many risk loci fail to colocalize with expression quantitative trait loci (eQTLs), potentially due to limited GWAS and eQTL analysis power or cellular heterogeneity. Population-scale single-cell RNA-sequencing (scRNA-seq) datasets are emerging, enabling mapping of eQTLs in different cell types (sc-eQTLs). Compared to eQTL data from bulk tissues (bk-eQTLs), sc-eQTL datasets are smaller. We propose a joint model of bk-eQTLs as a weighted sum of sc-eQTLs (JOBS) from constituent cell types to improve power. Applying JOBS to One1K1K and eQTLGen data, we identify 586% more eQTLs, matching the power of 4× the sample sizes of OneK1K. Integrating sc-eQTLs with GWAS data creates an atlas for 14 immune-mediated disorders, colocalizing 29.9% or 32.2% more loci than using sc-eQTL or bk-eQTL alone. Extending JOBS, we develop a drug-repurposing pipeline and identify novel drugs validated by real-world data. © 2025 The Author(s)

关键词： autoimmune disease bulk eQTL colocalization drug repurposing GWAS scRNAseq sequencing design single cell eQTL transcriptome

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A good gut feeling on Sarml-mediated axon degeneration

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Protein & Cell 2021年第8期12卷 596-598页

作者： Victoria E.von Saucken David J.Simon Department of Biochemistry Weill Cornell Medical College1300 York AvenueNew YorkNY 10065USA Tri-lnstitutional MD-PhD Program Weill Cornell MedicineRockefeller UniversityMemorial Sloan Kettering Cancer Center1300 York AvenueNew YorkNY 10065USA

Axons,the cable-like projections of neurons,experience a wide range of stressors throughout their *** result of any one of these challenges can be catastrophic,promoting degeneration of the *** degeneration is an active signaling process observed in traumatic brain injury,chemotherapy-induced peripheral neuropathies,and neu-rodegenerative disease(Simon and Watkins,2018;Coleman and Hoeke,2020).

关键词： degeneration chemotherapy traumatic

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Autophagy in hepatitis C virus-host interactions:Potential roles and therapeutic targets for liver-associated diseases

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World Journal of Gastroenterology 2014年第19期20卷 5773-5793页

作者： Po-Yuan Ke Steve S-L Chen Institute of Biomedical Sciences Academia Sinica Department of Biochemistry and Molecular Biology Graduate Institute of Biomedical Sciencesand Molecular Medicine Research CenterCollege of MedicineChang Gung University Liver Research Center Chang-Gung Memorial Hospital PhD Program in Translational Medicine Kaohsiung Medical UniversityKaohsiung 80708 and Academia Sinica

Autophagy is a lysosome-associated,degradative process that catabolizes cytosolic components to recycle nutrients for further use and maintain cell *** C virus(HCV)is a major cause of chronic hepatitis,which often leads to end-stage liverassociated diseases and is a significant burden on worldwide public *** lines of evidence indicate that autophagy plays an important role in promoting the HCV life cycle in host ***,the diverse impacts of autophagy on a variety of signaling pathways in HCV-infected cells suggest that the autophagic process is required for balancing HCVhost cell interactions and involved in the pathogenesis of HCV-related liver ***,the detailed molecular mechanism underlying how HCV activates autophagy to benefit viral growth is still ***,how the autophagic response contributes to disease progression in HCV-infected cells remains largely ***,in this review,we overview the interplay between autophagy and the HCV life cycle and propose possible mechanisms by which autophagy may promote the pathogenesis of HCVassociated chronic liver ***,we outline the related studies on how autophagy interplays with HCV replication and discuss the possible implications of autophagy and viral replication in the progression of HCV-induced liver diseases,e.g.,steatosis and hepatocellular ***,we explore the potential therapeutics that target autophagy to cure HCV infection and its related liver diseases.

关键词： Autophagy Hepatitis C virus Steatosis Cirrhosis Hepatocellular carcinoma

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