Wiley最新文献

Background and aims: The hallmark of NAFLD or hepatic steatosis is characterized by lipid droplet (LD) accumulation in hepatocytes. Autophagy may have profound effects on lipid metabolism and innate immune response. However, how innate immune activation may regulate the autophagic degradation of intracellular LDs remains elusive.

Approach and results: A mouse model of a high-fat diet-induced NASH was used in the myeloid-specific stimulator of interferon genes (STING) knockout or STING/yes-associated protein (YAP) double knockout mice. Liver injury, lipid accumulation, lipid droplet proteins, autophagic genes, chromatin immunoprecipitation coupled with massively parallel sequencing, and RNA-Seq were assessed in vivo and in vitro . We found that high-fat diet-induced oxidative stress activates STING and YAP pathways in hepatic macrophages. The acrophage STING deficiency (myeloid-specific STING knockout) enhances nuclear YAP activity, reduces lipid accumulation, and increases autophagy-related proteins ATG5, ATG7, and light chain 3B but diminishes LD protein perilipin 2 expression. However, disruption of STING and YAP (myeloid STING and YAP double knockout) increases serum alanine aminotransferase and triglyceride levels and reduces β-fatty acid oxidation gene expression but augments perilipin 2 levels, exacerbating high-fat diet-induced lipid deposition. Chromatin immunoprecipitation coupled with massively parallel sequencing reveals that macrophage YAP targets transmembrane protein 205 and activates AMP-activated protein kinase α, which interacts with hepatocyte mitofusin 2 and induces protein disulfide isomerase activation. Protein disulfide isomerase activates hypoxia-inducible factor-1α signaling, increases autophagosome colocalization with LDs, and promotes the degradation of perilipin 2 by interacting with chaperone-mediated autophagy chaperone HSC70.

Conclusions: The macrophage STING-YAP axis controls hepatic steatosis by reprogramming lipid metabolism in a transmembrane protein 205/mitofusin 2/protein disulfide isomerase-dependent pathway. These findings highlight the regulatory mechanism of the macrophage STING-driven YAP activity on lipid control.

The Arabidopsis BLADE-ON-PETIOLE (BOP) genes are primarily known for their roles in regulating leaf and floral patterning. However, the broader functions of BOPs in regulating plant traits remain largely unexplored. In this study, we investigated the role of the Gossypium hirsutum BOP1 gene in the regulation of fibre length and plant height through the brassinosteroid (BR) signalling pathway. Transgenic cotton plants overexpressing GhBOP1 display shorter fibre lengths and reduced plant height compared to the wild type. Conversely, GhBOP1 knockdown led to increased plant height and longer fibre, indicating a connection with phenotypes influenced by the BR pathway. Our genetic evidence supports the notion that GhBOP1 regulates fibre length and plant height in a GhBES1-dependent manner, with GhBES1 being a major transcription factor in the BR signalling pathway. Yeast two-hybrid, luciferase complementation assay and pull-down assay results demonstrated a direct interaction between GhBOP1 and GhSUMO1, potentially forming protein complexes with GhBES1. In vitro and in vivo SUMOylation analyses revealed that GhBOP1 functions in an E3 ligase-like manner to mediate GhBES1 SUMOylation and subsequent degradation. Therefore, our study not only uncovers a novel mechanism of GhBES1 SUMOylation but also provides significant insights into how GhBOP1 regulates fibre length and plant height by controlling GhBES1 accumulation.

Objective: To understand the etiological landscape and phenotypic differences between 2 developmental and epileptic encephalopathy (DEE) syndromes: DEE with spike-wave activation in sleep (DEE-SWAS) and epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS).

Methods: All patients fulfilled International League Against Epilepsy (ILAE) DEE-SWAS or EE-SWAS criteria with a Core cohort (n = 91) drawn from our Epilepsy Genetics research program, together with 10 etiologically solved patients referred by collaborators in the Expanded cohort (n = 101). Detailed phenotyping and analysis of molecular genetic results were performed. We compared the phenotypic features of individuals with DEE-SWAS and EE-SWAS. Brain-specific gene co-expression analysis was performed for D/EE-SWAS genes.

Results: We identified the etiology in 42/91 (46%) patients in our Core cohort, including 29/44 (66%) with DEE-SWAS and 13/47 (28%) with EE-SWAS. A genetic etiology was identified in 31/91 (34%). D/EE-SWAS genes were highly co-expressed in brain, highlighting the importance of channelopathies and transcriptional regulators. Structural etiologies were found in 12/91 (13%) individuals. We identified 10 novel D/EE-SWAS genes with a range of functions: ATP1A2, CACNA1A, FOXP1, GRIN1, KCNMA1, KCNQ3, PPFIA3, PUF60, SETD1B, and ZBTB18, and 2 novel copy number variants, 17p11.2 duplication and 5q22 deletion. Although developmental regression patterns were similar in both syndromes, DEE-SWAS was associated with a longer duration of epilepsy and poorer intellectual outcome than EE-SWAS.

Interpretation: DEE-SWAS and EE-SWAS have highly heterogeneous genetic and structural etiologies. Phenotypic analysis highlights valuable clinical differences between DEE-SWAS and EE-SWAS which inform clinical care and prognostic counseling. Our etiological findings pave the way for the development of precision therapies. ANN NEUROL 2024;96:932-943.

Structural variations (SVs) are major genetic variants that can be involved in the origin, adaptation and domestication of species. However, the identification and characterization of SVs in Spinacia species are rare due to the lack of a pan-genome. Here, we report eight chromosome-scale assemblies of cultivated spinach and its two wild species. After integration with five existing assemblies, we constructed a comprehensive Spinacia pan-genome and identified 193 661 pan-SVs, which were genotyped in 452 Spinacia accessions. Our pan-SVs enabled genome-wide association study identified signals associated with sex and clarified the evolutionary direction of spinach. Most sex-linked SVs (86%) were biased to occur on the Y chromosome during the evolution of the sex-linked region, resulting in reduced Y-linked gene expression. The frequency of pan-SVs among Spinacia accessions further illustrated the contribution of these SVs to domestication, such as bolting time and seed dormancy. Furthermore, compared with SNPs, pan-SVs act as efficient variants in genomic selection (GS) because of their ability to capture missing heritability information and higher prediction accuracy. Overall, this study provides a valuable resource for spinach genomics and highlights the potential utility of pan-SV in crop improvement and breeding programmes.

Objective: To develop a multiparametric machine-learning (ML) framework using high-resolution 3 dimensional (3D) magnetic resonance (MR) fingerprinting (MRF) data for quantitative characterization of focal cortical dysplasia (FCD).

Materials: We included 119 subjects, 33 patients with focal epilepsy and histopathologically confirmed FCD, 60 age- and gender-matched healthy controls (HCs), and 26 disease controls (DCs). Subjects underwent whole-brain 3 Tesla MRF acquisition, the reconstruction of which generated T1 and T2 relaxometry maps. A 3D region of interest was manually created for each lesion, and z-score normalization using HC data was performed. We conducted 2D classification with ensemble models using MRF T1 and T2 mean and standard deviation from gray matter and white matter for FCD versus controls. Subtype classification additionally incorporated entropy and uniformity of MRF metrics, as well as morphometric features from the morphometric analysis program (MAP). We translated 2D results to individual probabilities using the percentage of slices above an adaptive threshold. These probabilities and clinical variables were input into a support vector machine for individual-level classification. Fivefold cross-validation was performed and performance metrics were reported using receiver-operating-characteristic-curve analyses.

Results: FCD versus HC classification yielded mean sensitivity, specificity, and accuracy of 0.945, 0.980, and 0.962, respectively; FCD versus DC classification achieved 0.918, 0.965, and 0.939. In comparison, visual review of the clinical magnetic resonance imaging (MRI) detected 48% (16/33) of the lesions by official radiology report. In the subgroup where both clinical MRI and MAP were negative, the MRF-ML models correctly distinguished FCD patients from HCs and DCs in 98.3% of cross-validation trials. Type II versus non-type-II classification exhibited mean sensitivity, specificity, and accuracy of 0.835, 0.823, and 0.83, respectively; type IIa versus IIb classification showed 0.85, 0.9, and 0.87. In comparison, the transmantle sign was present in 58% (7/12) of the IIb cases.

Interpretation: The MRF-ML framework presented in this study demonstrated strong efficacy in noninvasively classifying FCD from normal cortex and distinguishing FCD subtypes. ANN NEUROL 2024;96:944-957.

Cold stress is a major abiotic stress that threatens maize (Zea mays L.) production worldwide. Understanding the molecular mechanisms underlying cold tolerance is crucial for breeding resilient maize varieties. Tonoplast intrinsic proteins (TIPs) are a subfamily of aquaporins in plants. Here, we report that TIP family proteins are involved in maize cold tolerance. The expression of most TIP genes was responsive to cold stress. Overexpressing TIP2;1, TIP3;2 or TIP4;3 reduced the cold tolerance of maize seedlings, while loss-of-function mutants of TIP4;3 exhibited enhanced cold tolerance. Candidate gene-based association analysis revealed that a 328-bp transposon insertion in the promoter region of TIP4;3 was strongly associated with maize cold tolerance. This transposon insertion conferred cold tolerance by repressing TIP4;3 expression through increased methylation of its promoter region. Moreover, TIP4;3 was found to suppress stomatal closure and facilitate reactive oxygen species (ROS) accumulation under cold stress, thereby inhibiting the expression of cold-responsive genes, including DEHYDRATION-RESPONSIVE ELEMENT BINDING FACTOR 1 (DREB1) genes and a subset of peroxidase genes, ultimately attenuating maize cold tolerance. This study thus elucidates the mechanism underlying TIP-mediated cold tolerance and identifies a favourable TIP4;3 allele as a potential genetic resource for breeding cold-tolerant maize varieties.

Eukaryotic translation initiation factors (eIFs) are the primary targets for overcoming RNA virus resistance in plants. In a previous study, we mapped a BjeIF2Bβ from Brassica juncea representing a new class of plant virus resistance genes associated with resistance to Turnip mosaic virus (TuMV). However, the mechanism underlying eIF2Bβ-mediated virus resistance remains unclear. In this study, we discovered that the natural variation of BjeIF2Bβ in the allopolyploid B. juncea was inherited from one of its ancestors, B. rapa. By editing of eIF2Bβ, we were able to confer resistance to TuMV in B. juncea and in its sister species of B. napus. Additionally, we identified an N⁶-methyladenosine (m⁶A) demethylation factor, BjALKBH9B, for interaction with BjeIF2Bβ, where BjALKBH9B co-localized with both BjeIF2Bβ and TuMV. Furthermore, BjeIF2Bβ recruits BjALKBH9B to modify the m⁶A status of TuMV viral coat protein RNA, which lacks the ALKB homologue in its genomic RNA, thereby affecting viral infection. Our findings have applications for improving virus resistance in the Brassicaceae family through natural variation or genome editing of the eIF2Bβ. Moreover, we uncovered a non-canonical translational control of viral mRNA in the host plant.