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New genetic tools to define the pathophysiology of inborn errors of cobalamin metabolism impacting mammalian development

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Differentiation 2025年 143卷 100868页

作者： Chern, Tiffany Tong, Xuefei Bauer, William G. Quispe-Parra, David J. Gao, Xia Gerner-Mauro, Kamryn N. Poché, Ross A. Department of Integrative Physiology Baylor College of Medicine Houston 77030 TX United States Graduate Program in Molecular Physiology and Biophysics Baylor College of Medicine Houston 77030 TX United States Development Disease Models and Therapeutics Graduate Program Baylor College of Medicine Houston 77030 TX United States Genetics and Genomics Graduate Program Baylor College of Medicine Houston 77030 TX United States Cancer and Cell Biology Graduate Program Baylor College of Medicine Houston 77030 TX United States Children's Nutrition Research Center Department of Pediatrics Baylor College of Medicine 1100 Bates Ave. Houston 77030 TX United States Department of Molecular and Cellular Biology Baylor College of Medicine Houston TX United States

The congenital, autosomal recessive disorder combined methylmalonic acidemia and homocystinuria – cblC type, is the most common inborn error of cobalamin (vitamin B12) metabolism. In its early onset form, cblC profou...

The congenital, autosomal recessive disorder combined methylmalonic acidemia and homocystinuria – cblC type, is the most common inborn error of cobalamin (vitamin B₁₂) metabolism. In its early onset form, cblC profoundly impacts fetal development of the central nervous system, hematopoietic system, and other tissues. Previously, mutations in the MMACHC gene, which encodes a protein required for the intracellular trafficking and enzymatic processing of free cobalamin into active coenzyme forms, were found to cause cblC. These coenzymes are required in two metabolic pathways which produce either succinyl-CoA in the mitochondria or methionine in the cytosol. However, due to a lack of sufficient animal models, the exact pathophysiology of cblC remains unknown. Moreover, there is evidence to suggest that MMACHC may have roles outside of cobalamin metabolism and that cobalamin itself may be required for additional, unknown metabolic pathways. Here, we report the generation and characterization of three new mouse lines aimed at further defining the role of MMACHC and cobalamin in mammalian development. CRISPR/Cas9 genome editing was used to develop an HA-tagged version of Mmachc, which will aid in affinity purification and spatiotemporal localization of the MMACHC protein. To clarify which metabolic perturbations downstream of Mmachc loss give rise to tissue-specific developmental defects, we also created floxed alleles for both methionine synthase (Mtr) and methylmalonyl-CoA mutase (Mmut), which are the only known cobalamin dependent enzymes in mammals. In total, these new mouse models significantly expand upon the repertoire of genetic reagents to clarify the pathophysiology of cblC as well as define both the canonical and hypothesized noncanonical roles of MMACHC in mammalian development. © 2025 International Society of Differentiation

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scNanoCOOL-seq:a long-read single-cell sequencing method for multi-omics profiling within individual cells

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细胞研究（英文版） 2023年第11期33卷 879-882页

作者： Jianli Lin Xiaohui Xue Yan Wang Yuan Zhou Jian Wu Haoling Xie Mengya Liu Lu Wen Fuchou Tang Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijingChina Biomedical Pioneering Innovation Center School of Life SciencesPeking UniversityBeijingChina Beijing Advanced Innovation Center for Genomics(ICG) Ministry of Education Key Laboratory of Cell Proliferation and DifferentiationBeijingChina Biomedical Pioneering Innovation Center School of Life SciencesPeking UniversityBeijingChina Beijing Advanced Innovation Center for Genomics(ICG) Ministry of Education Key Laboratory of Cell Proliferation and DifferentiationBeijingChina PKU-Tsinghua-NIBS Graduate Program Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijingChina Biomedical Pioneering Innovation Center School of Life SciencesPeking UniversityBeijingChina Beijing Advanced Innovation Center for Genomics(ICG) Ministry of Education Key Laboratory of Cell Proliferation and DifferentiationBeijingChina Biomedical Pioneering Innovation Center School of Life SciencesPeking UniversityBeijingChina Beijing Tongren Eye Center Beijing Tongren HospitalCapital Medical UniversityBeijing Ophthalmology & Visual Science Key LabBeijingChina Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijingChina Biomedical Pioneering Innovation Center School of Life SciencesPeking UniversityBeijingChina Beijing Advanced Innovation Center for Genomics(ICG) Ministry of Education Key Laboratory of Cell Proliferation and DifferentiationBeijingChina PKU-Tsinghua-NIBS Graduate Program Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijingChina

Dear Editor, Single-cell multi-omics sequencing technologies provide a first step towards a more comprehensive understanding of cell type-specific gene regulation,expanding our ability to systematically explore cellular diversity and heterogeneity.1 Based on nucleo-some occupancy and methylome sequencing(NOMe-seq)and bisulfite sequencing(BS-seq),we and others previously developed single-cell NOMe-seq(scNOMe-seq)and single-cell chromatin overall omic-scale landscape sequencing(scCOOL-seq).1,2 Employ-ing a different strategy,scCOOL-seq/scNOMe-seq has several advantages over other existing single-cell muti-omics sequencing methods(Supplementary information,Note S1).

关键词： Chromatin analysis Gene expression profiling Methylation analysis

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Sex-based Disparities in Brain Aging: A Focus on Parkinson's Disease

arXiv

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arXiv 2023年

作者： Beheshti, Iman Booth, Samuel Ko, Ji Hyun Department of Human Anatomy and Cell Science University of Manitoba WinnipegMB Canada Kleysen Institute for Advanced Medicine Health Science Centre WinnipegMB Canada Graduate Program in Biomedical Engineering University of Manitoba WinnipegMB Canada

INTRODUCTION: Parkinson’s disease (PD) is linked to faster brain aging. Sex is recognized as an important factor in PD, such that males are twice as likely as females to have the disease and have more severe symptoms and a faster progression rate. Despite previous research, there remains a significant gap in understanding the function of sex in the process of brain aging in PD patients. METHODS: The T1-weighted MRI-driven brain-predicted age difference (i.e., brain-PAD: the actual age subtracted from the brain-predicted age) was computed in a group of 373 PD patients (mean age ± SD: 61.37 ± 9.81, age range: 33–85, 34% female) from the Parkinson’s Progression Marker Initiative database using a robust brain-age estimation framework that was trained on 949 healthy subjects. Linear regression models were used to investigate the association between brain-PAD and clinical variables in PD, stratified by sex. All female PD patients were used in the correlational analysis while the same number of males were selected based on propensity score matching method considering age, education level, age of symptom onset, and clinical symptom severity. RESULTS: Despite both patient groups being matched for demographics, motor and non-motor symptoms, it was observed that males with Parkinson's disease (PD-M) exhibited a significantly higher mean brain age-delta than their female counterparts (PD-F) (t(256)= 2.50, p = 0.012). In the propensity score-matched PD-M group (PD-M*), brain-PAD was found to be associated with a decline in general cognition, a worse degree of sleep behavior disorder, reduced visuospatial acuity, and caudate atrophy. Conversely, no significant links were observed between these factors and brain-PAD in the PD-F group. DISCUSSION: Having 'older' looking brains in PD-M than PD-F supports the idea that sex plays a vital function in PD, such that the PD mechanism may be different in males and females. This study has the potential to broaden our understanding of dissim

关键词： Machine learning

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N-phenylmaleimide induces bioenergetic switch and suppresses tumor growth in glioblastoma tumorspheres by inhibiting SLC25A11

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Cancer cell International 2025年第1期25卷 1-15页

作者： Cho, Hye Joung Yoo, Jihwan Choi, Ran Joo Lee, Jae-Seon Kim, Ryong Nam Park, Junseong Moon, Ju Hyung Kim, Eui Hyun Teo, Wan-Yee Chang, Jong Hee Kim, Soo-Youl Kang, Seok-Gu Department of Neurosurgery Brain Tumor Center Severance Hospital Yonsei University College of Medicine Seoul South Korea Brain Tumor Translational Research Laboratory Department of Biomedical Sciences Yonsei University College of Medicine Seoul South Korea Department of Neurosurgery Gangnam Severance Hospital Yonsei University College of Medicine Seoul South Korea Department of Medical Science Yonsei University Graduate School Seoul South Korea Department of Division of Cancer Biology National Cancer Center Goyang South Korea Department of College of Medicine The Catholic University of Korea Catholic Medical Center Seoul South Korea Cancer and Stem Cell Biology Program Duke-NUS Medical School Singapore Singapore Institute of Molecular and Cell Biology A*STAR Singapore Singapore Brain Research Institute Yonsei University College of Medicine Seoul 03722 South Korea

Background: Glioblastoma (GBM) is a highly resistant tumor, and targeting its bioenergetics could be a potential treatment strategy. GBM cells depend on cytosolic nicotinamide adenine dinucleotide (NADH), which is transported into the mitochondria via the malate-aspartate shuttle (MAS) for ATP production. N-phenylmaleimide (KN612) is a MAS inhibitor that targets SLC25A11, an antiporter protein of the MAS. Therefore, this study investigated the effects of KN612 in GBM treatment using in vitro and in vivo models. Methods: We examined the biological effects of KN612 in GBM tumorspheres (TSs), including its effects on cell viability, ATP level, cell cycle, stemness, invasive properties, energy metabolic pathways, and transcriptomes. Additionally, we investigated the in vivo efficacy of KN612 in a mouse orthotopic xenograft model. Results: Transcriptomic analysis showed that SLC25A11 mRNA expression was significantly higher in GBM TSs than in normal human astrocytes. Additionally, siRNA-mediated SLC25A11 knockdown and KN612-mediated MAS inhibition decreased the oxygen consumption rate, ATP levels, mitochondrial activity, and cell viability in GBM TSs and decreased the stemness and invasion ability of GBM cells. Moreover, gene ontology functional annotation indicated that KN612 treatment inhibited cell-cycle and mitotic processes. Furthermore, KN612 treatment reduced tumor size and prolonged survival in an orthotopic xenograft model. Conclusions: Targeting GBM bioenergetics using KN612 may represent a novel and effective approach for GBM treatment. © The Author(s) 2025.

关键词： Bioenergetics Glioblastoma KN612 Malate-aspartate shuttle SLC25A11

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A derivation error that affects carbon balance models exists in the current implementation of the modified Arrhenius function (vol 231, pg 2371, 2021)

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NEW PHYTOLOGIST 2021年第6期231卷 2395-2397页

作者： Murphy, Bridget K. Stinziano, Joseph R. Department of Biology University of Toronto Mississauga Mississauga ON L5L 1C6 Canada Graduate Program in Cell and Systems Biology University of Toronto Toronto ON M5S 1A1 Canada Department of Biology University of New Mexico Albuquerque NM 87131 USA

Understanding biological temperature responses is crucial to predicting global carbon fluxes. The current approach to modelling temperature responses of photosynthetic capacity in large scale modelling efforts uses a modified Arrhenius equation. We rederived the modified Arrhenius equation from the source publication from 1942 and uncovered a missing term that was dropped by 2002. We compare fitted temperature response parameters between the correct and incorrect derivation of the modified Arrhenius equation. We find that most parameters are minimally affected, though activation energy is impacted quite substantially. We then scaled the impact of these small errors to whole plant carbon balance and found that the impact of the rederivation of the modified Arrhenius equation on modelled daily carbon gain causes a meaningful deviation of c. 18% day−1. This suggests that the error in the derivation of the modified Arrhenius equation has impacted the accuracy of predictions of carbon fluxes at larger scales since > 40% of Earth System Models contain the erroneous derivation. We recommend that the derivation error be corrected in modelling efforts moving forward.

关键词： Arrhenius carbon balance gas exchange modelling photosynthesis temperature

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Bacterial Mobility and Motility in Porous Media Mimicked By Microspheres

SSRN

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SSRN 2022年

作者： Shrestha, Diksha Ou, Jun Rogers, Ariel Jereb, Amani Wang, Yong Department of Physics Cell and Molecular Graduate Program Materials Science and Engineering Program University of Arkansas FayettevilleAR72701 United States Department of Environmental Resources Engineering Mechanical Engineering Program California State Polytechnic University Humboldt ArcataCA95521 United States

Bacterial motion in porous media are essential for their survival, proper functioning, and variousapplications. Here we investigated the motion of Escherichia coli bacteria in microsphere-mimicked porousmedia. We observed reduced bacterial velocity and enhanced directional changes of bacteria as the densityof microspheres increased, while such changes happened mostly around the microspheres and due to thecollisions with the microspheres. More importantly, we established and quantified the correlation betweenthe bacterial trapping in porous media and the geometric confinement imposed by the microspheres. In addition,numerical simulations showed that the active Brownian motion model in the presence of microspheresresulted in bacterial motion that are consistent with the experimental observations. Our study suggested thatit is important to distinguish the ability of bacteria to move easily – bacterial mobility – from the abilityof bacteria to move independently – bacteria motility. Our results showed that bacterial motility remainssimilar in porous media, but bacterial mobility was significantly affected by the pore-scale confinement. © 2022, The Authors. All rights reserved.

关键词： Microspheres

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Enhanced diabetic wound healing using platelet-derived extracellular vesicles and reduced graphene oxide in polymer-coordinated hydrogels

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Journal of Nanobiotechnology 2023年第1期21卷 1-17页

作者： Hao, Ping-Chien Burnouf, Thierry Chiang, Chih-Wei Jheng, Pei-Ru Szunerits, Sabine Yang, Jen-Chang Chuang, Er-Yuan Graduate Institute of Biomedical Materials and Tissue Engineering College of Biomedical Engineering Taipei Medical University Taipei11031 Taiwan International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University Taipei11031 Taiwan Graduate Institute of Biomedical Electronics and Bioinformatics National Taiwan University Taipei10617 Taiwan Department of Orthopedics Taipei Medical University Hospital Taipei11031 Taiwan Univ. Lille CNRS Centrale Lille Univ. Polytechnique Hauts-de-France UMR 8520 IEMN LilleF- 59000 France Graduate Institute of Nanomedicine and Medical Engineering College of Biomedical Engineering Taipei Medical University Taipei110-52 Taiwan Cell Physiology and Molecular Image Research Center Taipei Medical University-Wan Fang Hospital Taipei11696 Taiwan Precision Medicine and Translational Cancer Research Center Taipei Medical University Hospital Taipei11031 Taiwan

Impaired wound healing is a significant complication of diabetes. Platelet-derived extracellular vesicles (pEVs), rich in growth factors and cytokines, show promise as a powerful biotherapy to modulate cellular proliferation, angiogenesis, immunomodulation, and inflammation. For practical home-based wound therapy, however, pEVs should be incorporated into wound bandages with careful attention to delivery strategies. In this work, a gelatin-alginate hydrogel (GelAlg) loaded with reduced graphene oxide (rGO) was fabricated, and its potential as a diabetic wound dressing was investigated. The GelAlg@rGO-pEV gel exhibited excellent mechanical stability and biocompatibility in vitro, with promising macrophage polarization and reactive oxygen species (ROS)-scavenging capability. In vitro cell migration experiments were complemented by in vivo investigations using a streptozotocin-induced diabetic rat wound model. When exposed to near-infrared light at 2 W cm− 2, the GelAlg@rGO-pEV hydrogel effectively decreased the expression of inflammatory biomarkers, regulated immune response, promoted angiogenesis, and enhanced diabetic wound healing. Interestingly, the GelAlg@rGO-pEV hydrogel also increased the expression of heat shock proteins involved in cellular protective pathways. These findings suggest that the engineered GelAlg@rGO-pEV hydrogel has the potential to serve as a wound dressing that can modulate immune responses, inflammation, angiogenesis, and follicle regeneration in diabetic wounds, potentially leading to accelerated healing of chronic wounds. © 2023, BioMed Central Ltd., part of Springer Nature.

关键词： Platelets

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Atmospheric humidity regulates same-sex mating in Candida albicans through the trehalose and osmotic signaling pathways

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Science China(Life Sciences) 2023年第8期66卷 1915-1929页

作者： Chao Li Li Tao Guobo Guan Zhangyue Guan Austin M.Perry Tianren Hu Jian Bing Ming Xu Clarissa J.Nobile Guanghua Huang Department of Infectious Diseases Huashan HospitalShanghai Institute of Infectious Disease and Biosecurity and State Key Laboratory of Genetic EngineeringSchool of Life SciencesFudan UniversityShanghai 200438China State Key Laboratory of Mycology Institute of MicrobiologyChinese Academy of SciencesBeijing 100101China Department of Molecular and Cell Biology University of CaliforniaMercedMerced CA 95343USA Quantitative and Systems Biology Graduate Program University of CaliforniaMercedMerced CA 95343USA Health Sciences Research Institute University of CaliforniaMercedMerced CA 95343USA Shanghai Engineering Research Center of Industrial Microorganisms Shanghai 200438China Shanghai Huashen Institute of Microbes and Infections Shanghai 200052China

Sexual reproduction is prevalent in eukaryotic organisms and plays a critical role in the evolution of new traits and in the generation of genetic *** factors often have a direct impact on the occurrence and frequency of sexual reproduction in *** regulatory effects of atmospheric relative humidity(RH)on sexual reproduction and pathogenesis in plant fungal pathogens and in soil fungi have been extensively ***,the knowledge of how RH regulates the lifecycles of human fungal pathogens is *** this study,we report that low atmospheric RH promotes the development of mating projections and same-sex(homothallic)mating in the human fungal pathogen Candida *** RH causes water loss in *** cells,which results in osmotic stress and the generation of intracellular reactive oxygen species(ROS)and *** water transporting aquaporin Aqy1,and the G-protein coupled receptor Gpr1 function as cell surface sensors of changes in atmospheric *** of the trehalose metabolic pathway by inactivating trehalose synthase or trehalase promotes same-sex mating in *** by increasing osmotic or ROS stresses,*** trehalose and ROS signal the Hog1-osmotic and Hsf1-Hsp90 signaling pathways to regulate the mating ***,therefore,propose that the cell surface sensors Aqy1 and Gpr1,intracellular trehalose and ROS,and the Hog1-osmotic and Hsf1-Hsp90 signaling pathways function coordinately to regulate sexual mating in response to low atmospheric RH conditions in ***.

关键词： atmospheric relative humidity sexual reproduction same-sex mating Candida albicans trehalose metabolism osmotic stress

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A novel anode of gold nanoparticle coated Au nanorod arrays for nonenzymatic glucose fuel cells

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Journal of Power Sources 2024年 590卷

作者： Ting, Ya-Chun Lin, Ying-Ting Wang, Gou-Jen Department of Mechanical Engineering National Chung-Hsing University Taichung40227 Taiwan Program in Tissue Engineering and Regenerative Medicine National Chung-Hsing University Taichung40227 Taiwan Graduate Institute of Medical Engineering National Chung-Hsing University Taichung40227 Taiwan Regenerative Medicine and Cell Therapy Research Center Kaohsiung Medical University Kaohsiung80708 Taiwan

In this study, we propose a novel nonenzymatic glucose fuel cell (GFC) with an anode of gold nanoparticle coated Au nanorod arrays (AuNPs@AuNRA). The anode is fabricated through anodic aluminum oxide production, photolithographic patterning, core nickel nanorods electroforming, immersing gold, and gold nanoparticle electrodeposition. A double-chamber GFC, consisting of the proposed anode, a graphene-modified glassy carbon cathode, and a Nafion proton-exchange membrane separating the anode and cathode, is constructed. Experimental results reveal that the proposed GFC can produce a maximum power density of 822 μW/cm2, a Voc of 0.8 V, and an Isc density of 5.15 mA/cm2 at a glucose concentration of 0.2 M. The energy conversion efficiency of the proposed nonenzymatic GFC reaches 51.6%, which can be attributed to the high catalyzation area of the AuNPs@AuNRA anode. Thus, the proposed nonenzymatic GFC exhibit promising feasibility in applications. © 2023 The Authors

关键词： Anodes

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SAME-cell, SINGLE-cell DETECTION OF PROTEIN ISOFORMS AND NUCLEIC ACIDS 25

SAME-CELL, SINGLE-CELL DETECTION OF PROTEIN ISOFORMS AND NUC...

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25th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2021

作者： Gomez Martinez, Ana E. Rosas-Canyelles, Elisabet Modzelewski, Andrew J. Geldert, Alisha Gopal, Anjali He, Lin Herr, Amy E. Department of Bioengineering University of California Berkeley BerkeleyCA United States UC Berkeley-UCSF Graduate Program in Bioengineering United States Division of Cellular and Developmental Biology Department of Molecular & Cell Biology University of California BerkeleyCA United States

ISBN: (纸本)9781733419031

Single-cell 'omics is advancing rapidly, but there are gaps in linking nucleic acids to proteins in their myriad forms. To surmount this gap, we describe a microfluidic device that reports information on nucleic acids and proteoforms, or proteins that arise from a variety of modifications to nucleic acids or proteins, which are detected by immunoblotting (triBlot). The triBlot fractionates nuclei from the cytoplasm, allowing analysis of cytoplasmic proteoforms. Then, nuclei-laden regions are laser excised to perform PCR/RT-qPCR. We correlate DNA, mRNA, and protein expression from the same few cells, a step forward in 'omics that measure diverse protein forms. © 2021 MicroTAS 2021 - 25th International Conference on Miniaturized Systems for Chemistry and Life Sciences. All rights reserved.

关键词： Proteins

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