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"Tian, Na"
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Inducible and reversible RNA N6-methyladenosine editing
RNA modifications, including N
6
-methyladenosine (m
6
A), have been reported to regulate fundamental RNA processes and properties, and directly linked to various human diseases. Methods enabling temporal and transcript/locus-specific editing of specific RNA modifications are essential, but still limited, to dissect the dynamic and context-dependent functions of these epigenetic modifications. Here, we develop a chemically inducible and reversible RNA m
6
A modification editing platform integrating chemically induced proximity (CIP) and CRISPR methods. We show that m
6
A editing can be temporally controlled at specific sites of individual RNA transcripts by the addition or removal of the CIP inducer, abscisic acid (ABA), in the system. By incorporating a photo-caged ABA, a light-controlled version of m
6
A editing platform can be developed. We expect that this platform and strategy can be generally applied to edit other RNA modifications in addition to m
6
A.
RNA modifications, including N6-methyladenosine (m6A), have been reported to regulate fundamental RNA processes and properties, and directly linked to various human diseases. Here, the authors develop a chemically inducible and reversible RNA m6A modification editing platform integrating chemically induced proximity (CIP) and CRISPR methods.
Journal Article
Genome-wide identification and expression pattern analysis of lipoxygenase gene family in banana
The LOX genes have been identified and characterized in many plant species, but studies on the banana LOX genes are very limited. In this study, we respectively identified 18 MaLOX, 11 MbLOX, and 12 MiLOX genes from the
Musa acuminata
,
M. balbisiana
and
M. itinerans
genome data, investigated their gene structures and characterized the physicochemical properties of their encoded proteins. Banana
LOXs
showed a preference for using and ending with G/C and their encoded proteins can be classified into 9-LOX, Type I 13-LOX and Type II 13-LOX subfamilies. The expansion of the
MaLOXs
might result from the combined actions of genome-wide, tandem, and segmental duplications. However, tandem and segmental duplications contribute to the expansion of
MbLOXs
. Transcriptome data based gene expression analysis showed that
MaLOX1
,
4
, and
7
were highly expressed in fruit and their expression levels were significantly regulated by ethylene. And 11, 12 and 7
MaLOXs
were found to be low temperature-, high temperature-, and
Fusarium oxysporum
f. sp.
Cubense
tropical race 4 (
Foc
TR4)-responsive, respectively.
MaLOX8
,
9
and
13
are responsive to all the three stresses,
MaLOX4
and
MaLOX12
are high temperature- and
Foc
TR4-responsive;
MaLOX6
and
MaLOX17
are significantly induced by low temperature and
Foc
TR4; and the expression of
MaLOX7
and
MaLOX16
are only affected by high temperature. Quantitative real-time PCR (qRT-PCR) analysis revealed that the expression levels of several
MaLOXs
are regulated by MeJA and
Foc
TR4, indicating that they can increase the resistance of banana by regulating the JA pathway. Additionally, the weighted gene co-expression network analysis (WGCNA) of
MaLOXs
revealed 3 models respectively for 5 (
MaLOX7
-
11
), 3 (
MaLOX6
,
13
, and
17
), and 1 (MaLOX
12
) MaLOX genes. Our findings can provide valuable information for the characterization, evolution, diversity and functionality of MaLOX, MbLOX and MiLOX genes and are helpful for understanding the roles of
LOXs
in banana growth and development and adaptations to different stresses.
Journal Article
Deactivation of excitatory neurons in the prelimbic cortex via Cdk5 promotes pain sensation and anxiety
The medial prefrontal cortex (mPFC) is implicated in processing sensory-discriminative and affective pain. Nonetheless, the underlying mechanisms are poorly understood. Here we demonstrate a role for excitatory neurons in the prelimbic cortex (PL), a sub-region of mPFC, in the regulation of pain sensation and anxiety-like behaviours. Using a chronic inflammatory pain model, we show that lesion of the PL contralateral but not ipsilateral to the inflamed paw attenuates hyperalgesia and anxiety-like behaviours in rats. Optogenetic activation of contralateral PL excitatory neurons exerts analgesic and anxiolytic effects in mice subjected to chronic pain, whereas inhibition is anxiogenic in naive mice. The intrinsic excitability of contralateral PL excitatory neurons is decreased in chronic pain rats; knocking down cyclin-dependent kinase 5 reverses this deactivation and alleviates behavioural impairments. Together, our findings provide novel insights into the role of PL excitatory neurons in the regulation of sensory and affective pain.
The medial prefrontal cortex (mPFC) is implicated in pain regulation, yet the underlying mechanisms are poorly understood. Here the authors establish a critical role for mPFC in regulating pain sensation and pain-related anxiety, mediated by activation of the cyclin-dependent kinase 5 signalling pathway.
Journal Article
The complete chloroplast genome sequence of Epipremnum aureum and its comparative analysis among eight Araceae species
Epipremnum aureum is an important foliage plant in the Araceae family. In this study, we have sequenced the complete chloroplast genome of E. aureum by using Illumina Hiseq sequencing platforms. This genome is a double-stranded circular DNA sequence of 164,831 bp that contains 35.8% GC. The two inverted repeats (IRa and IRb; 26,606 bp) are spaced by a small single-copy region (22,868 bp) and a large single-copy region (88,751 bp). The chloroplast genome has 131 (113 unique) functional genes, including 86 (79 unique) protein-coding genes, 37 (30 unique) tRNA genes, and eight (four unique) rRNA genes. Tandem repeats comprise the majority of the 43 long repetitive sequences. In addition, 111 simple sequence repeats are present, with mononucleotides being the most common type and di- and tetranucleotides being infrequent events. Positive selection pressure on rps12 in the E. aureum chloroplast has been demonstrated via synonymous and nonsynonymous substitution rates and selection pressure sites analyses. Ycf15 and infA are pseudogenes in this species. We constructed a Maximum Likelihood phylogenetic tree based on the complete chloroplast genomes of 38 species from 13 families. Those results strongly indicated that E. aureum is positioned as the sister of Colocasia esculenta within the Araceae family. This work may provide information for further study of the molecular phylogenetic relationships within Araceae, as well as molecular markers and breeding novel varieties by chloroplast genetic-transformation of E. aureum in particular.
Journal Article
APP lysine 612 lactylation ameliorates amyloid pathology and memory decline in Alzheimer’s disease
Posttranslational modification (PTM) of the amyloid precursor protein (APP) plays a critical role in Alzheimer's disease (AD). Recent evidence reveals that lactylation modification, as a novel PTM, is implicated in the occurrence and development of AD. However, whether and how APP lactylation contributes to both the pathogenesis and cognitive function in AD remains unknown. Here, we observed a reduction in APP lactylation in AD patients and AD model mice and cells. Proteomic mass spectrometry analysis further identified lysine 612 (APP-K612la) as a crucial site for APP lactylation, influencing APP amyloidogenic processing. A lactyl-mimicking mutant (APPK612T) reduced amyloid-β peptide (Aβ) generation and slowed down cognitive deficits in vivo. Mechanistically, APPK612T appeared to facilitate APP trafficking and metabolism. However, lactylated APP entering the endosome inhibited its binding to BACE1, suppressing subsequent cleavage. Instead, it promoted protein interaction between APP and CD2-associated protein (CD2AP), thereby accelerating the endosomal-lysosomal degradation pathway of APP. In the APP23/PS45 double-transgenic mouse model of AD, APP-Kla was susceptible to L-lactate regulation, which reduced Aβ pathology and repaired spatial learning and memory deficits. Thus, these findings suggest that targeting APP lactylation may be a promising therapeutic strategy for AD in humans.
Journal Article
Implanting oxophilic metal in PtRu nanowires for hydrogen oxidation catalysis
Bimetallic PtRu are promising electrocatalysts for hydrogen oxidation reaction in anion exchange membrane fuel cell, where the activity and stability are still unsatisfying. Here, PtRu nanowires were implanted with a series of oxophilic metal atoms (named as i-M-PR), significantly enhancing alkaline hydrogen oxidation reaction (HOR) activity and stability. With the dual doping of In and Zn atoms, the i-ZnIn-PR/C shows mass activity of 10.2 A mg
Pt+Ru
−1
at 50 mV, largely surpassing that of commercial Pt/C (0.27 A mg
Pt
−1
) and PtRu/C (1.24 A mg
Pt+Ru
−1
). More importantly, the peak power density and specific power density are as high as 1.84 W cm
−2
and 18.4 W mg
Pt+Ru
−1
with a low loading (0.1 mg cm
−2
) anion exchange membrane fuel cell. Advanced experimental characterizations and theoretical calculations collectively suggest that dual doping with In and Zn atoms optimizes the binding strengths of intermediates and promotes CO oxidation, enhancing the HOR performances. This work deepens the understanding of developing novel alloy catalysts, which will attract immediate interest in materials, chemistry, energy and beyond.
Designing an efficient electrocatalyst of hydrogen oxidation reaction is highly critical for anion exchange membrane fuel cells. Here the authors report implanting oxophilic metal atoms in PtRu nanowires to significantly improve the mass activity, stability, and resistance to CO-poisoning for hydrogen oxidation.
Journal Article
Synthesis of Tetrahexahedral Platinum Nanocrystals with High-Index Facets and High Electro-Oxidation Activity
The shapes of noble metal nanocrystals (NCs) are usually defined by polyhedra that are enclosed by {111} and {100} facets, such as cubes, tetrahedra, and octahedra. Platinum NCs of unusual tetrahexahedral (THH) shape were prepared at high yield by an electrochemical treatment of Pt nanospheres supported on glassy carbon by a square-wave potential. The single-crystal THH NC is enclosed by 24 high-index facets such as {730}, {210}, and/or {520} surfaces that have a large density of atomic steps and dangling bonds. These high-energy surfaces are stable thermally (to 800°C) and chemically and exhibit much enhanced (up to 400%) catalytic activity for equivalent Pt surface areas for electro-oxidation of small organic fuels such as formic acid and ethanol.
Journal Article
Biodegradable Nanoprobe for NIR‐II Fluorescence Image‐Guided Surgery and Enhanced Breast Cancer Radiotherapy Efficacy
Positive resection margin frequently exists in breast‐conserving treatment (BCT) of early‐stage breast cancer, and insufficient therapeutic efficacy is common during radiotherapy (RT) in advanced breast cancer patients. Moreover, a multimodal nanotherapy platform is urgently required for precision cancer medicine. Therefore, a biodegradable cyclic RGD pentapeptide/hollow virus‐like gadolinium (Gd)‐based indocyanine green (R&HV‐Gd@ICG) nanoprobe is developed to improve fluorescence image‐guided surgery and breast cancer RT efficacy. R&HV‐Gd exhibits remarkably improved aqueous stability, tumor retention, and target specificity of ICG, and achieves outstanding magnetic resonance/second near‐infrared (NIR‐II) window multimodal imaging in vivo. The nanoprobe‐based NIR‐II fluorescence image guidance facilitates complete tumor resection, improves the overall mouse survival rate, and effectively discriminates between benign and malignant breast tissues in spontaneous breast cancer transgenic mice (area under the curve = 0.978; 95% confidence interval: 0.952, 1.0). Moreover, introducing the nanoprobe to tumors generated more reactive oxygen species under X‐ray irradiation, improved RT sensitivity, and reduced mouse tumor progression. Notably, the nanoprobe is biodegradable in vivo and exhibits accelerated bodily clearance, which is expected to reduce the potential long‐term inorganic nanoparticle toxicity. Overall, the nanoprobe provides a basis for developing precision breast cancer treatment strategies. A biodegradable diagnostic and therapeutic integrated nanoprobe is constructed for precise breast cancer treatment. The nanoprobe achieves accurate second near‐infrared (NIR‐II) fluorescence image‐guided surgical tumor resection and can be a radiotherapy (RT) sensitizer to enhance breast cancer RT efficacy. In addition, the nanoprobe exhibits in vivo biocompatibility and biodegradation.
Journal Article
TKT maintains intestinal ATP production and inhibits apoptosis-induced colitis
Inflammatory bowel disease (IBD) has a close association with transketolase (TKT) that links glycolysis and the pentose phosphate pathway (PPP). However, how TKT functions in the intestinal epithelium remains to be elucidated. To address this question, we specifically delete TKT in intestinal epithelial cells (IECs). IEC TKT-deficient mice are growth retarded and suffer from spontaneous colitis. TKT ablation brings about striking alterations of the intestine, including extensive mucosal erosion, aberrant tight junctions, impaired barrier function, and increased inflammatory cell infiltration. Mechanistically, TKT deficiency significantly accumulates PPP metabolites and decreases glycolytic metabolites, thereby reducing ATP production, which results in excessive apoptosis and defective intestinal barrier. Therefore, our data demonstrate that TKT serves as an essential guardian of intestinal integrity and barrier function as well as a potential therapeutic target for intestinal disorders.
Journal Article