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1.
Cell ; 175(2): 544-557.e16, 2018 10 04.
Article in English | MEDLINE | ID: mdl-30245013

ABSTRACT

A major challenge in genetics is to identify genetic variants driving natural phenotypic variation. However, current methods of genetic mapping have limited resolution. To address this challenge, we developed a CRISPR-Cas9-based high-throughput genome editing approach that can introduce thousands of specific genetic variants in a single experiment. This enabled us to study the fitness consequences of 16,006 natural genetic variants in yeast. We identified 572 variants with significant fitness differences in glucose media; these are highly enriched in promoters, particularly in transcription factor binding sites, while only 19.2% affect amino acid sequences. Strikingly, nearby variants nearly always favor the same parent's alleles, suggesting that lineage-specific selection is often driven by multiple clustered variants. In sum, our genome editing approach reveals the genetic architecture of fitness variation at single-base resolution and could be adapted to measure the effects of genome-wide genetic variation in any screen for cell survival or cell-sortable markers.


Subject(s)
Gene Editing/methods , High-Throughput Nucleotide Sequencing/methods , Saccharomyces cerevisiae/genetics , CRISPR-Cas Systems , Chromosome Mapping , Clustered Regularly Interspaced Short Palindromic Repeats/genetics , Genetic Variation/genetics , Genetic Vectors , Genome , Yeasts/genetics
2.
Mol Cell ; 82(4): 833-851.e11, 2022 02 17.
Article in English | MEDLINE | ID: mdl-35180428

ABSTRACT

HOTTIP lncRNA is highly expressed in acute myeloid leukemia (AML) driven by MLL rearrangements or NPM1 mutations to mediate HOXA topologically associated domain (TAD) formation and drive aberrant transcription. However, the mechanism through which HOTTIP accesses CCCTC-binding factor (CTCF) chromatin boundaries and regulates CTCF-mediated genome topology remains unknown. Here, we show that HOTTIP directly interacts with and regulates a fraction of CTCF-binding sites (CBSs) in the AML genome by recruiting CTCF/cohesin complex and R-loop-associated regulators to form R-loops. HOTTIP-mediated R-loops reinforce the CTCF boundary and facilitate formation of TADs to drive gene transcription. Either deleting CBS or targeting RNase H to eliminate R-loops in the boundary CBS of ß-catenin TAD impaired CTCF boundary activity, inhibited promoter/enhancer interactions, reduced ß-catenin target expression, and mitigated leukemogenesis in xenograft mouse models with aberrant HOTTIP expression. Thus, HOTTIP-mediated R-loop formation directly reinforces CTCF chromatin boundary activity and TAD integrity to drive oncogene transcription and leukemia development.


Subject(s)
CCCTC-Binding Factor/metabolism , Chromatin/metabolism , Leukemia, Myeloid, Acute/metabolism , R-Loop Structures , RNA, Long Noncoding/metabolism , beta Catenin/metabolism , Animals , CCCTC-Binding Factor/genetics , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Chromatin/genetics , Chromosomal Proteins, Non-Histone/genetics , Chromosomal Proteins, Non-Histone/metabolism , Gene Expression Regulation, Leukemic , HEK293 Cells , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Mice, Transgenic , RNA, Long Noncoding/genetics , Structure-Activity Relationship , Transcription, Genetic , Transcriptional Activation , beta Catenin/genetics , Cohesins
3.
Proc Natl Acad Sci U S A ; 121(10): e2306517121, 2024 Mar 05.
Article in English | MEDLINE | ID: mdl-38408236

ABSTRACT

China has committed to achieve net carbon neutrality by 2060 to combat global climate change, which will require unprecedented deployment of negative emissions technologies, renewable energies (RE), and complementary infrastructure. At terawatt-scale deployment, land use limitations interact with operational and economic features of power systems. To address this, we developed a spatially resolved resource assessment and power systems planning optimization that models a full year of power system operations, sub-provincial RE siting criteria, and transmission connections. Our modeling results show that wind and solar must be expanded to 2,000 to 3,900 GW each, with one plausible pathway leading to 300 GW/yr combined annual additions in 2046 to 2060, a three-fold increase from today. Over 80% of solar and 55% of wind is constructed within 100 km of major load centers when accounting for current policies regarding land use. Large-scale low-carbon systems must balance key trade-offs in land use, RE resource quality, grid integration, and costs. Under more restrictive RE siting policies, at least 740 GW of distributed solar would become economically feasible in regions with high demand, where utility-scale deployment is limited by competition with agricultural land. Effective planning and policy formulation are necessary to achieve China's climate goals.

4.
Nucleic Acids Res ; 52(10): 6066-6078, 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38738640

ABSTRACT

The Trans-Activator Receptor (TAR) RNA, located at the 5'-end untranslated region (5' UTR) of the human immunodeficiency virus type 1 (HIV-1), is pivotal in the virus's life cycle. As the initial functional domain, it folds during the transcription of viral mRNA. Although TAR's role in recruiting the Tat protein for trans-activation is established, the detailed kinetic mechanisms at play during early transcription, especially at points of temporary transcriptional pausing, remain elusive. Moreover, the precise physical processes of transcriptional pause and subsequent escape are not fully elucidated. This study focuses on the folding kinetics of TAR and the biological implications by integrating computer simulations of RNA folding during transcription with nuclear magnetic resonance (NMR) spectroscopy data. The findings reveal insights into the folding mechanism of a non-native intermediate that triggers transcriptional pause, along with different folding pathways leading to transcriptional pause and readthrough. The profiling of the cotranscriptional folding pathway and identification of kinetic structural intermediates reveal a novel mechanism for viral transcriptional regulation, which could pave the way for new antiviral drug designs targeting kinetic cotranscriptional folding pathways in viral RNAs.


Subject(s)
HIV Long Terminal Repeat , HIV-1 , RNA Folding , RNA, Viral , Transcription, Genetic , HIV-1/genetics , Kinetics , RNA, Viral/metabolism , RNA, Viral/chemistry , RNA, Viral/genetics , HIV Long Terminal Repeat/genetics , Nucleic Acid Conformation , Humans , 5' Untranslated Regions , Gene Expression Regulation, Viral , Magnetic Resonance Spectroscopy
5.
Proc Natl Acad Sci U S A ; 120(8): e2206694120, 2023 02 21.
Article in English | MEDLINE | ID: mdl-36795754

ABSTRACT

Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) BREA2 drives breast cancer metastasis by stabilizing the Notch1 intracellular domain (NICD1). Moreover, we reveal WW domain containing E3 ubiquitin protein ligase 2 (WWP2) as an E3 ligase for NICD1 at K1821 and a suppressor of breast cancer metastasis. Mechanistically, BREA2 impairs WWP2-NICD1 complex formation and in turn stabilizes NICD1, leading to Notch signaling activation and lung metastasis. BREA2 loss sensitizes breast cancer cells to inhibition of Notch signaling and suppresses the growth of breast cancer patient-derived xenograft tumors, highlighting its therapeutic potential in breast cancer. Taken together, these results reveal the lncRNA BREA2 as a putative regulator of Notch signaling and an oncogenic player driving breast cancer metastasis.


Subject(s)
Breast Neoplasms , Lung Neoplasms , RNA, Long Noncoding , Humans , Female , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Ubiquitination , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Lung Neoplasms/genetics , Breast Neoplasms/genetics , Receptor, Notch1/genetics , Receptor, Notch1/metabolism
6.
Proc Natl Acad Sci U S A ; 120(18): e2207537120, 2023 05 02.
Article in English | MEDLINE | ID: mdl-37098064

ABSTRACT

Policymakers must make management decisions despite incomplete knowledge and conflicting model projections. Little guidance exists for the rapid, representative, and unbiased collection of policy-relevant scientific input from independent modeling teams. Integrating approaches from decision analysis, expert judgment, and model aggregation, we convened multiple modeling teams to evaluate COVID-19 reopening strategies for a mid-sized United States county early in the pandemic. Projections from seventeen distinct models were inconsistent in magnitude but highly consistent in ranking interventions. The 6-mo-ahead aggregate projections were well in line with observed outbreaks in mid-sized US counties. The aggregate results showed that up to half the population could be infected with full workplace reopening, while workplace restrictions reduced median cumulative infections by 82%. Rankings of interventions were consistent across public health objectives, but there was a strong trade-off between public health outcomes and duration of workplace closures, and no win-win intermediate reopening strategies were identified. Between-model variation was high; the aggregate results thus provide valuable risk quantification for decision making. This approach can be applied to the evaluation of management interventions in any setting where models are used to inform decision making. This case study demonstrated the utility of our approach and was one of several multimodel efforts that laid the groundwork for the COVID-19 Scenario Modeling Hub, which has provided multiple rounds of real-time scenario projections for situational awareness and decision making to the Centers for Disease Control and Prevention since December 2020.


Subject(s)
COVID-19 , Humans , COVID-19/epidemiology , COVID-19/prevention & control , Uncertainty , Disease Outbreaks/prevention & control , Public Health , Pandemics/prevention & control
7.
J Biol Chem ; 300(8): 107554, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39002667

ABSTRACT

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, also exhibits nuclear genomic localization and is involved in DNA damage signaling. In this study, we investigated the impact of cGAS crotonylation on the regulation of the DNA damage response, particularly homologous recombination repair, following exposure to ionizing radiation (IR). Lysine 254 of cGAS is constitutively crotonylated by the CREB-binding protein; however, IR-induced DNA damage triggers sirtuin 3 (SIRT3)-mediated decrotonylation. Lysine 254 decrotonylation decreased the DNA-binding affinity of cGAS and inhibited its interaction with PARP1, promoting homologous recombination repair. Moreover, SIRT3 suppression led to homologous recombination repair inhibition and markedly sensitized cancer cells to IR and DNA-damaging chemicals, highlighting SIRT3 as a potential target for cancer therapy. Overall, this study revealed the crucial role of cGAS crotonylation in the DNA damage response. Furthermore, we propose that modulating cGAS and SIRT3 activities could be potential strategies for cancer therapy.


Subject(s)
DNA Damage , Nucleotidyltransferases , Poly (ADP-Ribose) Polymerase-1 , Recombinational DNA Repair , Sirtuin 3 , Humans , Nucleotidyltransferases/metabolism , Nucleotidyltransferases/genetics , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly (ADP-Ribose) Polymerase-1/genetics , Sirtuin 3/metabolism , Sirtuin 3/genetics , DNA/metabolism , Lysine/metabolism , Lysine/chemistry , Radiation, Ionizing , HEK293 Cells
8.
Am J Pathol ; 194(4): 599-611, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37838011

ABSTRACT

The pathology of atherosclerosis, a leading cause of mortality in patients with cardiovascular disease, involves inflammatory phenotypic changes in vascular endothelial cells. This study explored the role of the dedicator of cytokinesis (DOCK)-2 protein in atherosclerosis. Mice with deficiencies in low-density lipoprotein receptor and Dock2 (Ldlr-/-Dock2-/-) and controls (Ldlr-/-) were fed a high-fat diet (HFD) to induce atherosclerosis. In controls, Dock2 was increased in atherosclerotic lesions, with increased intercellular adhesion molecule (Icam)-1 and vascular cell adhesion molecule (Vcam)-1, after HFD for 4 weeks. Ldlr-/-Dock2-/- mice exhibited significantly decreased oil red O staining in both aortic roots and aortas compared to that in controls after HFD for 12 weeks. In control mice and in humans, Dock2 was highly expressed in the ECs of atherosclerotic lesions. Dock2 deficiency was associated with attenuation of Icam-1, Vcam-1, and monocyte chemoattractant protein (Mcp)-1 in the aortic roots of mice fed HFD. Findings in human vascular ECs in vitro suggested that DOCK2 was required in TNF-α-mediated expression of ICAM-1/VCAM-1/MCP-1. DOCK2 knockdown was associated with attenuated NF-κB phosphorylation with TNF-α, partially accounting for DOCK2-mediated vascular inflammation. With DOCK2 knockdown in human vascular ECs, TNF-α-mediated VCAM-1 promoter activity was inhibited. The findings from this study suggest the novel concept that DOCK2 promotes the pathogenesis of atherosclerosis by modulating inflammation in vascular ECs.


Subject(s)
Atherosclerosis , Endothelial Cells , Humans , Animals , Mice , Endothelial Cells/metabolism , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/metabolism , Tumor Necrosis Factor-alpha/metabolism , Vascular Cell Adhesion Molecule-1/metabolism , Atherosclerosis/pathology , NF-kappa B/metabolism , Inflammation/pathology , Guanine Nucleotide Exchange Factors/genetics , Guanine Nucleotide Exchange Factors/metabolism , GTPase-Activating Proteins/genetics , GTPase-Activating Proteins/metabolism
9.
Mol Psychiatry ; 2024 Aug 30.
Article in English | MEDLINE | ID: mdl-39215183

ABSTRACT

Educational attainment (EA), socioeconomic status (SES) and cognition are phenotypically and genetically linked to health outcomes. However, the role of copy number variations (CNVs) in influencing EA/SES/cognition remains unclear. Using a large-scale (n = 305,401) genome-wide CNV-level association analysis, we discovered 33 CNV loci significantly associated with EA/SES/cognition, 20 of which were novel (deletions at 2p22.2, 2p16.2, 2p12, 3p25.3, 4p15.2, 5p15.33, 5q21.1, 8p21.3, 9p21.1, 11p14.3, 13q12.13, 17q21.31, and 20q13.33, as well as duplications at 3q12.2, 3q23, 7p22.3, 8p23.1, 8p23.2, 17q12 (105 kb), and 19q13.32). The genes identified in gene-level tests were enriched in biological pathways such as neurodegeneration, telomere maintenance and axon guidance. Phenome-wide association studies further identified novel associations of EA/SES/cognition-associated CNVs with mental and physical diseases, such as 6q27 duplication with upper respiratory disease and 17q12 (105 kb) duplication with mood disorders. Our findings provide a genome-wide CNV profile for EA/SES/cognition and bridge their connections to health. The expanded candidate CNVs database and the residing genes would be a valuable resource for future studies aimed at uncovering the biological mechanisms underlying cognitive function and related clinical phenotypes.

10.
Circ Res ; 132(4): e78-e93, 2023 02 17.
Article in English | MEDLINE | ID: mdl-36688311

ABSTRACT

BACKGROUND: Macrophage activation plays a critical role in abdominal aortic aneurysm (AAA) development. However, molecular mechanisms controlling macrophage activation and vascular inflammation in AAA remain largely unknown. The objective of the study was to identify novel mechanisms underlying adenosine deaminase acting on RNA (ADAR1) function in macrophage activation and AAA formation. METHODS: Aortic transplantation was conducted to determine the importance of nonvascular ADAR1 in AAA development/dissection. Ang II (Angiotensin II) infusion of ApoE-/- mouse model combined with macrophage-specific knockout of ADAR1 was used to study ADAR1 macrophage-specific role in AAA formation/dissection. The relevance of macrophage ADAR1 to human AAA was examined using human aneurysm specimens. Moreover, a novel humanized AAA model was established to test the role of human macrophages in aneurysm formation in human arteries. RESULTS: Allograft transplantation of wild-type abdominal aortas to ADAR1+/- recipient mice significantly attenuated AAA formation, suggesting that nonvascular ADAR1 is essential for AAA development. ADAR1 deficiency in hematopoietic cells decreased the prevalence and severity of AAA while inhibited macrophage infiltration and aorta wall inflammation. ADAR1 deletion blocked the classic macrophage activation, diminished NF-κB (nuclear factor kappa B) signaling, and enhanced the expression of a number of anti-inflammatory microRNAs. Mechanistically, ADAR1 interacted with Drosha to promote its degradation, which attenuated Drosha-DGCR8 (DiGeorge syndrome critical region 8) interaction, and consequently inhibited pri- to pre-microRNA processing of microRNAs targeting IKKß, resulting in an increased IKKß (inhibitor of nuclear factor kappa-B) expression and enhanced NF-κB signaling. Significantly, ADAR1 was induced in macrophages and interacted with Drosha in human AAA lesions. Reconstitution of ADAR1-deficient, but not the wild type, human monocytes to immunodeficient mice blocked the aneurysm formation in transplanted human arteries. CONCLUSIONS: Macrophage ADAR1 promotes aneurysm formation in both mouse and human arteries through a novel mechanism, that is, Drosha protein degradation, which inhibits the processing of microRNAs targeting NF-kB signaling and thus elicits macrophage-mediated vascular inflammation in AAA.


Subject(s)
Aortic Aneurysm, Abdominal , MicroRNAs , Humans , Mice , Animals , NF-kappa B/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , I-kappa B Kinase/metabolism , Macrophage Activation , Mice, Knockout , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Aortic Aneurysm, Abdominal/metabolism , Aorta, Abdominal/metabolism , Inflammation/metabolism , Angiotensin II/metabolism , Disease Models, Animal , Mice, Inbred C57BL , Adenosine Deaminase/genetics , Adenosine Deaminase/metabolism
11.
EMBO Rep ; 24(10): e57032, 2023 10 09.
Article in English | MEDLINE | ID: mdl-37650863

ABSTRACT

Bromodomain-containing protein 4 (BRD4) is overexpressed and functionally implicated in various myeloid malignancies. However, the role of BRD4 in normal hematopoiesis remains largely unknown. Here, utilizing an inducible Brd4 knockout mouse model, we find that deletion of Brd4 (Brd4Δ/Δ ) in the hematopoietic system impairs hematopoietic stem cell (HSC) self-renewal and differentiation, which associates with cell cycle arrest and senescence. ATAC-seq analysis shows increased chromatin accessibility in Brd4Δ/Δ hematopoietic stem/progenitor cells (HSC/HPCs). Genome-wide mapping with cleavage under target and release using nuclease (CUT&RUN) assays demonstrate that increased global enrichment of H3K122ac and H3K4me3 in Brd4Δ/Δ HSC/HPCs is associated with the upregulation of senescence-specific genes. Interestingly, Brd4 deletion increases clipped H3 (cH3) which correlates with the upregulation of senescence-specific genes and results in a higher frequency of senescent HSC/HPCs. Re-expression of BRD4 reduces cH3 levels and rescues the senescence rate in Brd4Δ/Δ HSC/HPCs. This study unveils an important role of BRD4 in HSC/HPC function by preventing H3 clipping and suppressing senescence gene expression.


Subject(s)
Histones , Transcription Factors , Animals , Mice , Transcription Factors/genetics , Transcription Factors/metabolism , Histones/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Cellular Senescence/genetics , Hematopoietic Stem Cells/metabolism , Cell Differentiation , Hematopoiesis
12.
Article in English | MEDLINE | ID: mdl-38868940

ABSTRACT

BACKGROUND: Plasma concentration of PAI-1 (plasminogen activator inhibitor-1) correlates with arterial stiffness. Vascular smooth muscle cells (SMCs) express PAI-1, and the intrinsic stiffness of SMCs is a major determinant of total arterial stiffness. We hypothesized that PAI-1 promotes SMC stiffness by regulating the cytoskeleton and that pharmacological inhibition of PAI-1 decreases SMC and aortic stiffness. METHODS: PAI-039, a specific inhibitor of PAI-1, and small interfering RNA were used to inhibit PAI-1 expression in cultured human SMCs. Effects of PAI-1 inhibition on SMC stiffness, F-actin (filamentous actin) content, and cytoskeleton-modulating enzymes were assessed. WT (wild-type) and PAI-1-deficient murine SMCs were used to determine PAI-039 specificity. RNA sequencing was performed to determine the effects of PAI-039 on SMC gene expression. In vivo effects of PAI-039 were assessed by aortic pulse wave velocity. RESULTS: PAI-039 significantly reduced intrinsic stiffness of human SMCs, which was accompanied by a significant decrease in cytoplasmic F-actin content. PAI-1 gene knockdown also decreased cytoplasmic F-actin. PAI-1 inhibition significantly increased the activity of cofilin, an F-actin depolymerase, in WT murine SMCs, but not in PAI-1-deficient SMCs. RNA-sequencing analysis suggested that PAI-039 upregulates AMPK (AMP-activated protein kinase) signaling in SMCs, which was confirmed by Western blotting. Inhibition of AMPK prevented activation of cofilin by PAI-039. In mice, PAI-039 significantly decreased aortic stiffness and tunica media F-actin content without altering the elastin or collagen content. CONCLUSIONS: PAI-039 decreases intrinsic SMC stiffness and cytoplasmic stress fiber content. These effects are mediated by AMPK-dependent activation of cofilin. PAI-039 also decreases aortic stiffness in vivo. These findings suggest that PAI-1 is an important regulator of the SMC cytoskeleton and that pharmacological inhibition of PAI-1 has the potential to prevent and treat cardiovascular diseases involving arterial stiffening.

13.
Brain ; 147(3): 755-765, 2024 03 01.
Article in English | MEDLINE | ID: mdl-37850820

ABSTRACT

Recent studies have revealed that glioma-associated mesenchymal stem cells play instrumental roles in tumorigenesis and tumour progression and cannot be ignored as a cellular component of the glioma microenvironment. Nevertheless, the origin of these cells and their roles are poorly understood. The only relevant studies have shown that glioma-associated mesenchymal stem cells play a large role in promoting tumour proliferation, invasion and angiogenesis. This review provides a comprehensive summary of their discovery and definition, origin, differences from other tissue-derived mesenchymal stem cells, spatial distribution, functions and prognostic and therapeutic opportunities to deepen the understanding of these cells and provide new insight into the treatment of glioma.


Subject(s)
Brain Neoplasms , Glioma , Mesenchymal Stem Cells , Humans , Brain Neoplasms/pathology , Cell Proliferation , Glioma/pathology , Tumor Microenvironment
14.
Nucleic Acids Res ; 51(7): 3341-3356, 2023 04 24.
Article in English | MEDLINE | ID: mdl-36864729

ABSTRACT

RNA 3D structures are critical for understanding their functions. However, only a limited number of RNA structures have been experimentally solved, so computational prediction methods are highly desirable. Nevertheless, accurate prediction of RNA 3D structures, especially those containing multiway junctions, remains a significant challenge, mainly due to the complicated non-canonical base pairing and stacking interactions in the junction loops and the possible long-range interactions between loop structures. Here we present RNAJP ('RNA Junction Prediction'), a nucleotide- and helix-level coarse-grained model for the prediction of RNA 3D structures, particularly junction structures, from a given 2D structure. Through global sampling of the 3D arrangements of the helices in junctions using molecular dynamics simulations and in explicit consideration of non-canonical base pairing and base stacking interactions as well as long-range loop-loop interactions, the model can provide significantly improved predictions for multibranched junction structures than existing methods. Moreover, integrated with additional restraints from experiments, such as junction topology and long-range interactions, the model may serve as a useful structure generator for various applications.


Subject(s)
Molecular Dynamics Simulation , RNA , RNA/chemistry , Nucleic Acid Conformation , Base Pairing , Nucleotides
15.
Clin Microbiol Rev ; 36(1): e0005122, 2023 03 23.
Article in English | MEDLINE | ID: mdl-36648228

ABSTRACT

Talaromycosis is an invasive mycosis endemic in tropical and subtropical Asia and is caused by the pathogenic fungus Talaromyces marneffei. Approximately 17,300 cases of T. marneffei infection are diagnosed annually, and the reported mortality rate is extremely high (~1/3). Despite the devastating impact of talaromycosis on immunocompromised individuals, particularly HIV-positive persons, and the increase in reported occurrences in HIV-uninfected persons, diagnostic and therapeutic approaches for talaromycosis have received far too little attention worldwide. In 2021, scientists living in countries where talaromycosis is endemic raised a global demand for it to be recognized as a neglected tropical disease. Therefore, T. marneffei and the infectious disease induced by this fungus must be treated with concern. T. marneffei is a thermally dimorphic saprophytic fungus with a complicated mycological growth process that may produce various cell types in its life cycle, including conidia, hyphae, and yeast, all of which are associated with its pathogenicity. However, understanding of the pathogenic mechanism of T. marneffei has been limited until recently. To achieve a holistic view of T. marneffei and talaromycosis, the current knowledge about talaromycosis and research breakthroughs regarding T. marneffei growth biology are discussed in this review, along with the interaction of the fungus with environmental stimuli and the host immune response to fungal infection. Importantly, the future research directions required for understanding this serious infection and its causative pathogenic fungus are also emphasized to identify solutions that will alleviate the suffering of susceptible individuals worldwide.


Subject(s)
Mycoses , Talaromyces , Humans , Mycoses/diagnosis , Mycoses/drug therapy , Mycoses/epidemiology , Virulence
16.
Biophys J ; 123(17): 2647-2657, 2024 Sep 03.
Article in English | MEDLINE | ID: mdl-38297836

ABSTRACT

RNA molecules play a crucial role in various biological processes, with their functionality closely tied to their structures. The remarkable advancements in machine learning techniques for protein structure prediction have shown promise in the field of RNA structure prediction. In this perspective, we discuss the advances and challenges encountered in constructing machine learning-based models for RNA structure prediction. We explore topics including model building strategies, specific challenges involved in predicting RNA secondary (2D) and tertiary (3D) structures, and approaches to these challenges. In addition, we highlight the advantages and challenges of constructing RNA language models. Given the rapid advances of machine learning techniques, we anticipate that machine learning-based models will serve as important tools for predicting RNA structures, thereby enriching our understanding of RNA structures and their corresponding functions.


Subject(s)
Machine Learning , Nucleic Acid Conformation , RNA , RNA/chemistry , Models, Molecular
17.
J Mol Cell Cardiol ; 186: 45-56, 2024 01.
Article in English | MEDLINE | ID: mdl-37979444

ABSTRACT

Cardiac hypertrophy can develop to end-stage heart failure (HF), which inevitably leading to heart transplantation or death. Preserving cardiac function in cardiomyocytes (CMs) is essential for improving prognosis in hypertrophic cardiomyopathy (HCM) patients. Therefore, understanding transcriptomic heterogeneity of CMs in HCM would be indispensable to aid potential therapeutic targets investigation. We isolated primary CM from HCM patients who had extended septal myectomy, and obtained transcriptomes in 338 human primary CM with single-cell tagged reverse transcription (STRT-seq) approach. Our results revealed that CMs could be categorized into three subsets in nonfailing HCM heart: high energy synthesis cluster, high cellular metabolism cluster and intermediate cluster. The expression of electron transport chain (ETC) was up-regulated in larger-sized CMs from high energy synthesis cluster. Of note, we found the expression of Cytochrome c oxidase subunit 7B (COX7B), a subunit of Complex IV in ETC had trends of positively correlation with CMs size. Further, by assessing COX7B expression in HCM patients, we speculated that COX7B was compensatory up-regulated at early-stage but down-regulated in failing HCM heart. To test the hypothesis that COX7B might participate both in hypertrophy and HF progression, we used adeno associated virus 9 (AAV9) to mediate the expression of Cox7b in pressure overload-induced mice. Mice in vivo data supported that knockdown of Cox7b would accelerate HF and Cox7b overexpression could restore partial cardiac function in hypertrophy. Our result highlights targeting COX7B and preserving energy synthesis in hypertrophic CMs could be a promising translational direction for HF therapeutic strategy.


Subject(s)
Cardiomyopathy, Hypertrophic , Heart Failure , Heart Transplantation , Humans , Animals , Mice , Myocytes, Cardiac/metabolism , Heart Failure/genetics , Heart Failure/metabolism , Cardiomyopathy, Hypertrophic/metabolism , Cardiomegaly/genetics , Cardiomegaly/metabolism
18.
BMC Genomics ; 25(1): 593, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38867153

ABSTRACT

BACKGROUND: Terpenes are important components of plant aromas, and terpene synthases (TPSs) are the key enzymes driving terpene diversification. In this study, we characterized the volatile terpenes in five different Chrysanthemum nankingense tissues. In addition, genome-wide identification and expression analysis of TPS genes was conducted utilizing an improved chromosome-scale genome assembly and tissue-specific transcriptomes. The biochemical functions of three representative TPSs were also investigated. RESULTS: We identified tissue-specific volatile organic compound (VOC) and volatile terpene profiles. The improved Chrysanthemum nankingense genome assembly was high-quality, including a larger assembled size (3.26 Gb) and a better contig N50 length (3.18 Mb) compared to the old version. A total of 140 CnTPS genes were identified, with the majority representing the TPS-a and TPS-b subfamilies. The chromosomal distribution of these TPS genes was uneven, and 26 genes were included in biosynthetic gene clusters. Closely-related Chrysanthemum taxa were also found to contain diverse TPS genes, and the expression profiles of most CnTPSs were tissue-specific. The three investigated CnTPS enzymes exhibited versatile activities, suggesting multifunctionality. CONCLUSIONS: We systematically characterized the structure and diversity of TPS genes across the Chrysanthemum nankingense genome, as well as the potential biochemical functions of representative genes. Our results provide a basis for future studies of terpene biosynthesis in chrysanthemums, as well as for the breeding of improved chrysanthemum varieties.


Subject(s)
Alkyl and Aryl Transferases , Chrysanthemum , Genome, Plant , Multigene Family , Terpenes , Alkyl and Aryl Transferases/genetics , Alkyl and Aryl Transferases/metabolism , Chrysanthemum/genetics , Chrysanthemum/enzymology , Terpenes/metabolism , Phylogeny , Volatile Organic Compounds/metabolism , Plant Proteins/genetics , Plant Proteins/metabolism , Transcriptome
19.
BMC Genomics ; 25(1): 712, 2024 Jul 24.
Article in English | MEDLINE | ID: mdl-39044139

ABSTRACT

BACKGROUND: Yaks are a vital livestock in the Qinghai-Tibetan Plateau area for providing food products, maintaining sustainable ecosystems, and promoting cultural heritage. Because of uncontrolled mating, it is impossible to estimate inbreeding level of yak populations using the pedigree-based approaches. With the aims to accurately evaluate inbreeding level of two Chinese yak populations (Maiwa and Jiulong), we obtained genome-wide single nucleotide polymorphisms (SNPs) by DNA sequencing and calculated five SNP-by-SNP estimators ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text]), as well as two segment-based estimators of runs of homozygosity (ROH, [Formula: see text]) and homozygous-by-descent (HBD, [Formula: see text]). Functional implications were analyzed for the positional candidate genes located within the related genomic regions. RESULTS: A total of 151,675 and 190,955 high-quality SNPs were obtained from 71 Maiwa and 30 Jiulong yaks, respectively. Jiulong had greater genetic diversity than Maiwa in terms of allele frequency and nucleotide diversity. The two populations could be genetically distinguished by principal component analysis, with the mean differentiation index (Fst) of 0.0054. The greater genomic inbreeding levels of Maiwa yaks were consistently supported by all five SNP-by-SNP estimators. Based on simple proportion of homozygous SNPs ([Formula: see text]), a lower inbreeding level was indicated by three successfully sequenced old leather samples that may represent historical Maiwa yaks about five generations ago. There were 3304 ROH detected among all samples, with mean and median length of 1.97 Mb and 1.0 Mb, respectively. A total of 94 HBD segments were found among all samples, whereas 92 of them belonged to the shortest class with the mean length of 10.9 Kb. Based on the estimates of [Formula: see text] and [Formula: see text], however, there was no difference in inbreeding level between Maiwa and Jiulong yaks. Within the genomic regions with the significant Fst or enriched by ROH, we found several candidate genes and pathways that have been reported to be related to diverse production traits in farm animals. CONCLUSIONS: We successfully evaluated the genomic inbreeding level of two Chinese yak populations. Although different estimators resulted in inconsistent conclusions on their genomic inbreeding levels, our results may be helpful to implement the genetic conservation and utilization programs for the two yak populations.


Subject(s)
Genomics , Inbreeding , Polymorphism, Single Nucleotide , Animals , Cattle/genetics , Genomics/methods , China , Gene Frequency , Genetics, Population , Homozygote , Genome
20.
J Neurophysiol ; 2024 Aug 28.
Article in English | MEDLINE | ID: mdl-39196677

ABSTRACT

The pathological and physiological process of spinal cord injury is complex, and there is currently no effective treatment method. Magnetic stimulation is an emerging electromagnetic therapy method in recent years, and studies have shown its potential to reduce cell apoptosis. This study used an improved Allen's method to replicate an incomplete spinal cord injury rat model, and repetitive magnetic stimulation intervention was performed on the rats for 21 days. The research plan consists of two parts. The first part aims to observe the effects of rMS on motor function and neuronal cell apoptosis in rats. The BBB score results indicate that rMS promotes the recovery of motor function in rats; H&E staining showed that rMS improved spinal cord structural damage and inflammatory infiltration; TUNEL and NeuN staining suggest that rMS can reduce cell apoptosis and promote neuronal cell survival. The second part aims to explore the mechanism of action of rMS. Immunofluorescence staining showed that after rMS intervention, the positive counts of PI3K and Akt increased, while the positive counts of Caspase-3 decreased. Western blot showed that after rMS intervention, the expression of p-PI3K/PI3K, p-Akt/Akt, and Bcl-2 increased, while the expression of Bax and Caspase-3 decreased. In summary, rMS can significantly reduce cell apoptosis in the damaged spinal cord and promote neuronal cell survival. Its mechanism of action may be related to promoting the expression of PI3K/Akt pathway proteins, upregulating the anti apoptotic protein Bcl-2, downregulating the pro apoptotic protein Bax, and thereby inhibiting the expression of apoptotic protein Caspase-3.

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