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Genome and clonal hematopoiesis stability contrasts with immune,cfDNA,mitochondrial,and telomere length changes during short duration spaceflight

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Precision Clinical Medicine 2024年第1期7卷 1-13页

作者： J.Sebastian Garcia-Medina Karolina Sienkiewicz S.Anand Narayanan Eliah G.Overbey Kirill Grigorev Krista A.Ryon Marissa Burke Jacqueline Proszynski Braden Tierney Caleb M.Schmidt Nuria Mencia-Trinchant Remi Klotz Veronica Ortiz Jonathan Foox Christopher Chin Deena Najjar Irina Matei Irenaeus Chan Carlos Cruchaga Ashley Kleinman JangKeun Kim Alexander Lucaci Conor Loy Omary Mzava Iwijn De Vlaminck Anvita Singaraju Lynn E.Taylor Julian C.Schmidt Michael A.Schmidt Kelly Blease Juan Moreno Andrew Boddicker Junhua Zhao Bryan Lajoie Andrew Altomare Semyon Kruglyak Shawn Levy Min Yu Duane C.Hassane Susan M.Bailey Kelly Bolton Jaime Mateus Christopher E.Mason Department of physiology and Biophysics Weill Cornell MedicineCornell UniversityNew YorkNY 10021USA The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine Weill Cornell MedicineNew YorkNY 10021USA Department of Immunology Weill Cornell MedicineCornell UniversityNew YorkNY 10021USA Department of Stem Cell biology and Regenerative Medicine Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA Space Exploration Technologies Corporation HawthomeCA 90250USA Sovaris Aerospace BoulderCO 80302USA Advanced Pattern Analysis&Human Performance Group BoulderCO 80302USA Children's Cancer and Blood Foundation Laboratories Departments of Pediatrics and Cell and Developmental BiologyDrukier Institute for Children's HealthMeyer Cancer CenterWeill Cornell MedicineNew YorkNY 10021USA Meyer Cancer Center Weill Cornell MedicineNew YorkNY 10065USA Department of Nutrition and integrative physiology Florida State UniversityTallahasseeFL 32306USA Department of Systems Engineering Colorado State UniversityFort CollinsCO 80523USA Element Biosciences San DiegoCA 10055USA Department of Environmental and Radiological Health Sciences Colorado State UniversityFort CollinsCO 80523USA Cell and molecular biology Program Colorado State UniversityFort CollinsCO 80523USA BioAstra Inc New YorkNYUSA Washington University St Louis Oncology Division St.LouisMO 63100USA Meinig School of Biomedical Engineering Cornell UniversityIthacaNY 14853USA The Feil Family Brain and Mind Research Institute Weill Cornell MedicineNY 10021USA WorldQuant Initiative for Quantitative Prediction Weill Cornell MedicineNew YorkNY 10021USA

Background The Inspiration4(I4)mission,the first all-civilian orbital flight mission,investigated the physiological effects of short-duration spaceflight through a multi-omic approach.Despite advances,there remains much to learn about human adaptation to spaceflight's unique challenges,including microgravity,immune system perturbations,and radiation exposure.Methods To provide a detailed genetics analysis of the mission,we collected dried blood spots pre-,during,and post-flight for DNA extraction.Telomere length was measured by quantitative PCR,while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations.A robust bioinformatic pipeline was used for data analysis,including variant calling to assess mutational burden.Result Telomere elongation occurred during spaceflight and shortened after return to Earth.Cell-free DNA analysis revealed increased immune cell signatures post-flight.No significant clonal hematopoiesis of indeterminate potential(CHIP)or whole-genome instability was observed.The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight.Conclusion Our findings provide valuable insights into the physiological consequences of short-duration spaceflight,with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth.CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts,an understudied phenomenon as previous studies have focused on career astronauts.This study will serve as a reference point for future commercial and non-commercial spaceflight,low Earth orbit(LEO)missions,and deep-space exploration.

关键词： genomes clonal hematopoiesis stability immune mitochondria ribosomes spaceflight

Hibernation with rhythmicity:the circadian clock and hormonal adaptations of the hibernating Asiatic toads(Bufo gargarizans)

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integrative Zoology 2022年第4期17卷 656-669页

作者： Zhigang XIE Ibrahim M.AHMAD Lirong ZUO Feng XIAO Yongpeng WANG Dongming LI Zhejiang Academy of Agricultural Sciences HangzhouChina College of Chemistry and Life Science Zhejiang Normal UniversityJinhuaChina Ministry of Education Key Laboratory of molecular and cellular biology Key Laboratory of Animal PhysiologyBiochemistry and Molecular Biology of Hebei ProvinceCollege of Life SciencesHebei Normal UniversityShijiazhuangChina

Hibernation is one of the fundamental strategies in response to cold environmental temperatures.During hibernation,the endocrine and circadian systems ensure minimal expenditure of energy for survival.The circadian rhythms of key hormones,melatonin(MT),corticosterone(CORT),triiodothyronine(T3),and thyroxine(T4),and the underlying molecular regulatory mechanisms of hibernation have been well determined in mammals but not in ectotherms.Here,a terrestrial hibernating species,Asiatic toad(Bufo gargarizans),was employed to investigate the plasma CORT,MT,T3,and T4;and the retina,brain,and liver mRNA expression of the core clock genes,including circadian locomotor output cycles kaput(Clock),brain and muscle ARNT-like 1(Bmal1),cryptochrome(Cry)1 and 2,and period(Per)1 and 2,at 7-time points over a 24-h period under acute cold(1 day at 4℃),and hibernation(45 days at 4℃).Our results showed that the circadian rhythms of the core clock genes were rather unaffected by acute cold exposure in the retina,unlike the brain and liver.In contrast,during hibernation,the liver clock genes displayed significant circadian oscillations,while those in the retina and brain stopped ticking.Furthermore,plasma CORT expressed circadian oscillations in both groups,and T3 in acute cold exposure group,whereas T4 and MT did not.Our results reveal that the plasma CORT and the liver sustain rhythmicity when the brain was not,indicating that the liver clock along with the adrenal clock synergistically maintains the metabolic requirements to ensure basic survival in hibernating Asiatic toads.

关键词： Asiatic toad circadian rhythm clock genes cold exposure hibernation metabolic hormones

Global Landscape of Native Protein Complexes in Synechocystis sp.PCC 6803

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Genomics, Proteomics & Bioinformatics 2022年第4期20卷 715-727页

作者： Chen Xu Bing Wang Lin Yang Lucas Zhongming Hu Lanxing Yi Yaxuan Wang Shenglan Chen Andrew Emili Cuihong Wan School of Life Sciences and Hubei Key Laboratory of Genetic Regulation and integrative biology Central China Normal UniversityWuhan 430079China Donnelly Centre for cellular and Biomolecular Research University of TorontoTorontoON M5S 2E8Canada departments of biochemistry and biology Boston UniversityBostonMA 02215USA

Synechocystis sp.PCC 6803(hereafter:Synechocystis)is a model organism for studying photosynthesis,energy metabolism,and environmental stress.Although known as the first fully sequenced phototrophic organism,Synechocystis still has almost half of its proteome without functional annotations.In this study,by using co-fractionation coupled with liquid chromatographytandem mass spectrometry(LC-MS/MS),we define 291 multi-protein complexes,encompassing24,092 protein±protein interactions(PPIs)among 2062 distinct gene products.This information not only reveals the roles of photosynthesis in metabolism,cell motility,DNA repair,cell division,and other physiological processes,but also shows how protein functions vary from bacteria to higher plants due to changes in interaction partners.It also allows us to uncover the functions of hypothetical proteins,such as Sll0445,Sll0446,and Sll0447 involved in photosynthesis and cell motility,and Sll1334 involved in regulation of fatty acid biogenesis.Here we present the most extensive PPI data for Synechocystis so far,which provide critical insights into fundamental molecular mechanisms in cyanobacteria.

关键词： Protein–protein interaction Cyanobacterium Co-fractionation Photosynthesis Function prediction

Putting On The Breaks:Regulating Organelle Movements in Plant Cells

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Journal of integrative Plant biology 2012年第11期54卷 868-874页

作者： Julianna K.Vick Andreas Nebenfhr Department of biochemistry and cellular and molecular biology University of TennesseeKnoxvilleTN 37996USA

A striking characteristic of plant cells is that their organelles can move rapidly through the cell. This movement, commonly referred to as cytoplasmic streaming, has been observed for over 200 years, but we are only now beginning to decipher the mechanisms responsible for it. The identification of the myosin motor proteins responsible for these movements allows us to probe the regulatory events that coordinate organelle displacement with normal cell physiology. This review will highlight several recent developments that have provided new insight into the regulation of organelle movement, both at the cellular level and at the molecular level.

关键词： Cytoplasmic streaming cytoskeleton myosin organelle.

Optimized prime editing efficiently generates heritable mutations in maize

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Journal of integrative Plant biology 2023年第4期65卷 900-906页

作者： Dexin Qiao Junya Wang Min‐Hui Lu Cuiping Xin Yiping Chai Yuanyuan Jiang Wei Sun Zhenghong Cao Siyi Guo Xue‐Chen Wang Qi‐Jun Chen State Key Laboratory of Plant physiology and biochemistry College of Biological SciencesChina Agricultural UniversityBeijing 100193China Center for Crop Functional Genomics and molecular Breeding China Agricultural UniversityBeijing 100193China Collaborative Innovation Center of Crop Stress biology Henan ProvinceInstitute of Plant Stress BiologySchool of Life ScienceHenan UniversityKaifeng 475004China

Low efficiency is the main obstacle to using prime editing in maize(Zea mays).Recently,prime-editing efficiency was greatly improved in mammalian cells and rice(Oryza sativa)plants by engineering primeediting guide RNAs(pegRNAs),optimizing the prime editor(PE)protein,and manipulating cellular determinants of prime editing.In this study,we tested PEs optimized via these three strategies in maize.We demonstrated that the ePE5max system,composed of PEmax,epegRNAs(pegRNA-evopreQ.1),nicking single guide RNAs(sgRNAs),and MLH1dn,efficiently generated heritable mutations that conferred resistance to herbicides that inhibit 5-enolpyruvylshikimate-3-phosphate synthase(EPSPS),acetolactate synthase(ALS),or acetyl CoA carboxylase(ACCase)activity.Collectively,we demonstrate that the ePE5max system has sufficient efficiency to generate heritable(homozygous or heterozygous)mutations in maize target genes and that the main obstacle to using PEs in maize has thus been removed.

关键词： CRISPR/Cas epegRNAs herbicide resistance maize MLH1dn prime editing

Mitochondrial links between brain aging and Alzheimer’s disease

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Translational Neurodegeneration 2021年第3期10卷 421-431页

作者： Heather M.Wilkins Russell H.Swerdlow University of Kansas Alzheimer’s Disease Research Center Kansas CityKSUSA departments of Neurology University of Kansas Medical CenterKansas CityKSUSA departments of biochemistry and molecular biology Medical CenterUniversity of Kansas Medical CenterKansas CityUSA departments of molecular and integrative physiology Medical CenterUniversity of Kansas Medical CenterKansas CityKSUSA

Advancing age is a major risk factor for Alzheimer’s disease(AD).This raises the question of whether AD biology mechanistically diverges from aging biology or alternatively represents exaggerated aging.Correlative and modeling studies can inform this question,but without a frm grasp of what drives aging and AD it is difcult to defnitively resolve this quandary.This review speculates over the relevance of a particular hallmark of aging,mitochondrial function,to AD,and further provides background information that is pertinent to and provides perspective on this speculation.

关键词： Aging Alzheimer’s disease Mitochondria Mitochondrial DNA

Intervening pyruvate carboxylase stunts tumor growth by strengthening anti-tumor actions of tumor-associated macrophages

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Signal Transduction and Targeted Therapy 2022年第3期7卷 607-609页

作者： Yuxin Shu Nanfei Yang Nan Cheng Zhengyun Zou\Wenlong Zhang Yuncheng Bei Qian Shi Menghao Qin Wei-Guo Zhu Pingping Shen State Key Laboratory of Pharmaceutical Biotechnology and The Comprehensive Cancer Center Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolSchool of Life SciencesNanjing UniversityNanjing 210023PR Chino Guangdong Key Laboratory of Genome Instability and Human Disease Shenzhen University International Cancer CenterDepartment of Biochemistry and Molecular BiologyShenzhen UniversityShenzhen 518060PR China Department of cellular and integrative physiology The University of Texas Health Science Center at San Antonio7703 Floyd Curl DriveSan AntonioTX 78229-3904USA

Dear Editor,Tumor-associated macrophages(TAMs)are critical pro-tumor immunocytes and depletion of TAMs has been exploited for cancer therapy.1 However,the phenotypes and functions of TAMs are plastic,TAMs can also be effector cells by engulfing tumor cells and recruiting cytotoxic T cells,thus shaping the actions of TAMs is more scientific rational than depleting them indiscriminately.2 To promote the entry of reorienting TAMs into the clinical treatments of tumors,it is essential to explore the underline mechanisms controlling the anti-and pro-tumor activities of TAMs.

关键词： strengthening clinical rational

Trivalent Chromium Modulates Hexosamine Biosynthesis Pathway Transcriptional Activation of Cholesterol Synthesis and Insulin Resistance

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Open Journal of Endocrine and Metabolic Diseases 2013年第4期3卷 1-8页

作者： Brent A. Penque Lixuan Tackett Jeffrey S. Elmendorf departments of cellular and integrative physiology and biochemistry and molecular biology Centers for Diabetes Research and Membrane Biosciences Indiana University School of Medicine Indianapolis USA

Trivalent chromium has long been recognized to benefit carbohydrate and lipid metabolism. Given emerging evidence that suggests chromium improves insulin sensitivity through the maintenance of an optimal level of plasma membrane (PM) cholesterol, we delineated the role of this micronutrient in attenuating hyperinsulinemia-induced cholesterol biosynthesis and insulin resistance. Exposing 3T3-L1 adipocytes to physiological hyperinsulinemia (500 pM 12 h), resulted in a marked impairment in insulin-stimulated glucose transport. Concurrent treatment with chromium in the picolinate form (CrPic, 10 nM 16 h) prevented against glucose transport dysfunction. Insulin signaling was neither impaired by hyperinsulinemia nor amplified by chromium to promote this protective action. Instead, it was found that hyperinsulinemia promoted an increase in PM cholesterol content that was observed to impair the acute ability of insulin to stimulate GLUT4 redistribution to the PM. Chromium prevented against the accumulation of PM cholesterol. Mechanistically, hyperinsulinemia promoted increases in O-GlcNAc modification of specificity protein 1 (Sp1), known to engage a cholesterolgenic response. Subsequent chromatin immunoprecipitation and luciferase assays revealed that hyperinsulinemia increased the binding affinity of Sp1 to the promoter region of Hmgcr, encoding 3-hydroxy 3-methyl-glutaryl-CoA reductase (HMGR), as well as HMGR promoter activity. This resulted in gains in mRNA and protein content of HMGR, with resulting elevations in PM cholesterol content. Moreover, treatment with chromium prevented this transcriptional response. Together, these data suggest a mechanism whereby CrPic affords glycemic health through inhibition of a transcriptional cholesterolgenic program detrimental to insulin action.

关键词： 3T3-L1 Adipocytes GLUT4 HMG-CoA Reductase Hyperinsulinemia Sp1

Metabolic reprogram associated with epithelial-mesenchymal transition in tumor progression and metastasis

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Genes & Diseases 2020年第2期7卷 172-184页

作者： Yifan Wang Chenfang Dong Binhua P.Zhou Cancer Institute of integrative Medicine Zhejiang Academy of Traditional Chinese MedicineHangzhouZhejiang310012China Department of Pathology and Pathophysiology Department of Surgical Oncology(Breast Center)of the Second Affiliated HospitalZhejiang University School of MedicineHangzhou310058China departments of molecular and cellular biochemistry Markey Cancer CenterUniversity of Kentucky School of MedicineLexingtonKY40506USA

Epithelial-mesenchymal Transition(EMT)is a de-differentiation program that imparts tumor cells with the phenotypic and cellular plasticity required for drug resistance,metastasis,and recurrence.This dynamic and reversible events is governed by a network of EMT-transcription factors(EMT-TFs)through epigenetic regulation.Many chromatin modifying-enzymes utilize metabolic intermediates as cofactors or substrates;this suggests that EMT is subjected to the metabolic regulation.Conversely,EMT rewires metabolic program to accommodate cellular changes during EMT.Here we summarize the latest findings regarding the epigenetic regulation of EMT,and discuss the mutual interactions among metabolism,epigenetic regulation,and EMT.Finally,we provide perspectives of how this interplay contributes to cellular plasticity,which may result in the clinical manifestation of tumor heterogeneity.

关键词： Epigenetics Epithelialmesenchymal transition Heterogeneity Metabolism Plasticity