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Lin Xu

Publications and source records attributed to Lin Xu.

At least 19 recordsLinked to original sources
PubMed2026

Molecular mechanisms of natural de novo shoot organogenesis and their applications.

Natural de novo shoot organogenesis (DNSO) is the spontaneous regeneration of shoots from wound sites outside the shoot apical region through endogenous developmental programs. This regenerative capacity enables plants to recover from severe tissue damage by re-establishing the shoot-root axis. Here, we review current knowledge about the molecular mechanisms of natural DNSO, focusing on transcriptomic and physiological studies in model plants. Accumulating evidence suggests that natural DNSO proceeds through three sequential phases: (i) early wound responses, characterized by the activation of the WIND1-ESR1 module and the establishment of apical-basal auxin asymmetry; (ii) cellular proliferation driven by metabolic and cell-cycle reprogramming; and (iii) cytokinin-mediated establishment of shoot apical meristem identity. We also discuss how these mechanistic insights have been harnessed for practical applications, including tissue culture-free transformation systems such as the cut-dip-budding (CDB) method, and developmental reprogramming strategies that employ ectopic expression of developmental regulator (DR) genes to induce DNSO in otherwise recalcitrant species. Together, these advances illustrate how understanding natural regeneration can guide the development of simplified, broadly applicable plant transformation technologies.

Plant Shoots↗
PubMed2026

Hidden diversity of coronaviruses in high-altitude plateau mammals.

• Pikas and marmots from plateaus host divergent α- and β-CoVs, including the candidate subgenera Pibecovirus and Mabecovirus. • The plateau CoVs show distinctive genomic features (relocated HE gene, variable ORFs), indicating lineage-specific evolution. • High-altitude plateau ecosystems are a key yet understudied frontier of CoV evolution, warranting systematic surveillance.

Journal Article↗
PubMed2026

C9orf72-associated poly-GR in skeletal muscle leads to neuromuscular junction deficits and muscle atrophy.

Hexanucleotide repeat expansions in C9orf72 produce dipeptide repeat (DPR) proteins that are widely expressed, including in the nervous system and skeletal muscle. Among these DPRs, arginine-containing proteins, poly-GR and poly-PR, are toxic in the nervous system, but whether DPRs in skeletal muscle contribute to amyotrophic lateral sclerosis (ALS) pathogenesis is unclear. Here, we show that muscle-restricted expression of poly-GR drives motor deficits in mice, including muscle atrophy and neuromuscular junction (NMJ) deficits. Poly-GR in muscle interacted with the NMJ key organizer MuSK and promoted MuSK degradation, disrupting postsynaptic structure and impairing neuromuscular transmission. Importantly, a MuSK agonist antibody (X-17) stabilized NMJs and rescued neuromuscular transmission. Moreover, poly-GR in muscle activated the integrated stress response (ISR), elevating eIF2α phosphorylation and broadly suppressing protein translation. ISR inhibition with ISRIB restored translation and MuSK protein levels and ameliorated both muscle atrophy and NMJ deficits. These findings demonstrate that skeletal muscle actively contributes to C9orf72-ALS pathology. Targeting muscle with ISRIB offers a therapeutic strategy to preserve motor function in C9orf72-ALS.

Animals↗
PubMed2026

Targeting the METTL1/m7G axis as a therapeutic strategy in myeloid leukemia.

N7-methylguanosine (m7G), a prevalent modification in transfer RNAs (tRNAs), is primarily catalyzed by the methyltransferase METTL1. Although growing evidence supports a role for METTL1 in various tumors, its therapeutic potential and precise function in leukemia stem cell (LSC) homeostasis remain largely unexplored. Here, we identify METTL1 as a key regulator of LSC self-renewal and homing within bone marrow (BM) microenvironment through catalyzing m7G formation on a specific tRNA, tRNAPheGAA, thereby promoting leukemogenesis. Mechanistically, METTL1 loss significantly reduces m7G abundance and steady-state levels of tRNAPheGAA, leading to translation suppression and degradation of transcripts enriched with tRNAPheGAA-related codons, such as hematopoietic cell kinase (HCK). Decreased HCK expression disrupts CXCR4 signaling, impairing LSC self-renewal and BM homing. Therapeutically, we characterized a small-molecule METTL1 inhibitor (M1i; NSC137443), through high-throughput screening. Pharmacological inhibition of METTL1 demonstrated potent antitumor efficacy by reducing tRNA m7G levels and disrupting the tRNAPheGAA/HCK/CXCR4 cascade. Notably, targeting METTL1 significantly reduces LSC frequency, delays leukemogenesis, and prolongs survival in multiple acute myeloid leukemia models. Together, our findings establish a previously unrecognized role for METTL1 and its target tRNAPheGAA in LSC homeostasis and provide compelling proof-of-concept evidence that METTL1 is a druggable epitranscriptomic target for antileukemia therapy.

Humans↗
PubMed2026

Positive association between apolipoprotein B and colorectal cancer risk: Findings from a 14-year follow-up cohort study and Mendelian randomization analyses.

BACKGROUND: The effects of lipid traits on colorectal cancer (CRC) risk and the extent to which obesity may modify these effects remain unclear. OBJECTIVE: To examine the associations between lipid traits and CRC risk using an observational study and Mendelian randomization (MR) analyses, and the role of weight status in the potential associations. METHODS: In the Guangzhou Biobank Cohort Study (GBCS), lipid profiles were measured during 2003-2008, and CRC events were identified through record linkage with the cancer registry. MR analyses assessed the causal effects of lipid traits on CRC using a genome-wide association study meta-analysis of 185,616 Europeans. RESULTS: Among 28,576 GBCS participants followed until 2020, 599 CRC events occurred. Participants in the highest quartile of apolipoprotein B (apoB) had a higher CRC risk (hazard ratio [HR] 1.43, 95% CI 1.02-2.01). This association remained in those with overweight/obesity (HR 2.21, 95% CI 1.28-3.83). MR analyses supported a detrimental effect of apoB on CRC (odds ratio 1.12 per 1 SD, 95% CI 1.02-1.22). MR analyses also showed positive associations for total cholesterol and the apoB/apolipoprotein A-I ratio, which were not significant in the observational study. CONCLUSION: Higher apoB levels were associated with an increased CRC risk in both observational and MR analyses, suggesting a potential role of apoB in CRC prevention, especially among participants with overweight/obesity. However, the limitations of single-time lipid measurements and the use of different ancestries across study designs indicate the need for further research to confirm the robustness and generalizability of the findings.

Humans↗
PubMed2023

Single-swap editing for the correction of common Duchenne muscular dystrophy mutations.

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease of progressive muscle weakness and wasting caused by the absence of dystrophin protein. Current gene therapy approaches using antisense oligonucleotides require lifelong dosing and have limited efficacy in restoring dystrophin production. A gene editing approach could permanently correct the genome and restore dystrophin protein expression. Here, we describe single-swap editing, in which an adenine base editor edits a single base pair at a splice donor site or splice acceptor site to enable exon skipping or reframing. In human induced pluripotent stem cell-derived cardiomyocytes, we demonstrate that single-swap editing can enable beneficial exon skipping or reframing for the three most therapeutically relevant exons-DMD exons 45, 51, and 53-which could be beneficial for 30% of all DMD patients. Furthermore, an adeno-associated virus delivery method for base editing components can efficiently restore dystrophin production locally and systemically in skeletal and cardiac muscles of a DMD mouse model containing a deletion of Dmd exon 44. Our studies demonstrate single-swap editing as a potential gene editing therapy for common DMD mutations.

AAV↗
PubMed2007

Impaired hippocampal synaptic transmission and plasticity in mice lacking fibroblast growth factor 14.

Humans with an autosomal dominant missense mutation in fibroblast growth factor 14 (FGF14) have impaired cognitive abilities and slowly progressive spinocerebellar ataxia. To explore the mechanisms that may account for this phenotype, we show that synaptic transmission at hippocampal Schaffer collateral-CA1 synapses and short- and long-term potentiation are impaired in Fgf14-/- mice, indicating abnormalities in synaptic plasticity. Examination of CA1 synapses in Fgf14-/- mice show a significant reduction in the number of synaptic vesicles docked at presynaptic active zones and a significant synaptic fatigue/depression during high/low-frequency stimulation. In addition, mEPSC frequency, but not amplitude, is decreased in hippocampal neurons derived from Fgf14-/- mice. Furthermore, expression of selective synaptic proteins in Fgf14-/- mice was decreased. These findings suggest a novel role for FGF14 in regulating synaptic plasticity via presynaptic mechanisms by affecting the mobilization, trafficking, or docking of synaptic vesicles to presynaptic active zones.

Animals↗
PubMed2006

Transplantation of human neural stem cells exerts neuroprotection in a rat model of Parkinson's disease.

Neural stem cells (NSCs) possess high potencies of self-renewal and neuronal differentiation. We explored here whether transplantation of human NSCs cloned by v-myc gene transfer, HB1.F3 cells, is a feasible therapeutic option for Parkinson's disease. In vivo, green fluorescent protein-labeled HB1.F3 cells (200,000 viable cells in 3 microl of PBS) when stereotaxically transplanted (same-day lesion-transplant paradigm) into the 6-hydroxydopamine-lesioned striatum of rats significantly ameliorated parkinsonian behavioral symptoms compared with controls (vehicle, single bolus, or continuous minipump infusion of trophic factor, or killed cell grafts). Such graft-derived functional effects were accompanied by preservation of tyrosine hydroxylase (TH) immunoreactivity along the nigrostriatal pathway. Grafted HB1.F3 cells survived in the lesioned brain with some labeled with neuronal marker mitogen-activated protein 2 and decorated with synaptophysin-positive terminals. Furthermore, endogenous neurogenesis was activated in the subventricular zone of transplanted rats. To further explore the neuroprotective mechanisms underlying HB1.F3 cell transplantation, we performed cell culture studies and found that a modest number of HB1.F3 cells were TH and dopamine and cAMP-regulated phosphoprotein 32 positive, although most cells were nestin positive, suggesting a mixed population of mature and immature cells. Administration of the HB1.F3 supernatant to human derived dopaminergic SH-SY5Y cells and fetal rat ventral mesencephalic dopaminergic neurons protected against 6-hydroxydopamine neurotoxicity by suppressing apoptosis through Bcl-2 upregulation, which was blocked by anti-stem cell factor antibody alone, the phosphatidylinositol 3-kinase/Akt inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one] alone, or a combination of both. These results suggest that HB1.F3 cell transplantation exerts neuroprotective effects against dopaminergic depletion in vitro and in vivo because of trophic factor secretion and neuronal differentiation.

Animals↗
PubMed2006

Theoretical study on the electronic spectrum and the origin of remarkably large third-order nonlinear optical properties of organoimide derivatives of hexamolybdates.

Electronic spectrum of organoimide derivatives of hexamolybdates have first been calculated within the time-dependent density-functional theory in conjunction with Van Leeuwen-Baerends (LB94) exchange correlation potential, statistical average of orbital potentials (SAOP), and gradient-regulated connection potential (GRAC), respectively. The GRAC yields much better agreement with experiments for the excitation energies comparing with both LB94 and SAOP. The analysis of transition nature indicates that there is a significant difference between the diagonal and the orthogonal substituted derivatives. The static and dynamic third-order polarizabilities are calculated using time-dependent density-functional theory combined with the sum-over-states method. The results show that these derivatives possess remarkable large molecular third-order polarizabilities, especially for system 8 with -17882.6 x 10(-36) esu. This value is about 250 times that for the C(60) molecule. Adding the organoimide segment to the [Mo(6)O(19)](2-) can substantially increase the nu value. This variation can be traced to the different electronic transition characteristics between the derivatives of [Mo(6)O(19)](2-) and [Mo(6)O(19)](2-). For our studied systems, increasing the conjugation length and diagonal substituted are efficient ways to enhance the third-order polarizability. Thus, the organoimide derivatives of hexamolybdates may comprise a new promising class of nonlinear optical materials from the standpoint of large values, small dispersion behavior, and high transparency.

Algorithms↗
PubMed2006

Enriched environment treatment counteracts enhanced addictive and depressive-like behavior induced by prenatal chronic stress.

Prenatal stress can cause many long-term behavior changes in offspring, but whether prenatal stress can alter addictive behavior in offspring and postnatal enriched environment treatment (EE) can restore these changes are unknown. We reported here that prenatal chronic stress (10 unpredictable, 1 s, 0.8 mA foot-shocks per day during gestational days 13-19) enhanced morphine-induced (10 mg/kg, s.c., per day, 6 consecutive days) place preference. Moreover, prenatal chronic stress caused higher depressive-like behavior in forced swimming test in adult offspring. However, enriched environment housing treatment on postnatal days 22-52 counteracted both the abnormal behaviors alterations. This work observed a phenomenon that might contribute to the understanding of clinically important interactions among addiction, prenatal stress and enriched environment treatment. Postnatal enriched environment treatment might be an important therapeutic intervention in preventing the prenatal stress-induced addictive disorders.

Analysis of Variance↗
PubMed2006

Enriched environment treatment restores impaired hippocampal synaptic plasticity and cognitive deficits induced by prenatal chronic stress.

Prenatal stress can cause long-term effects on cognitive functions in offspring. Hippocampal synaptic plasticity, believed to be the mechanism underlying certain types of learning and memory, and known to be sensitive to behavioral stress, can be changed by prenatal stress. Whether enriched environment treatment (EE) in early postnatal periods can cause a recovery from these deficits is unknown. Experimental animals were Wistar rats. Prenatal stress was evoked by 10 foot shocks (0.8 mA for 1s, 2-3 min apart) in 30 min per day at gestational day 13-19. After weaning at postnatal day 22, experimental offspring were given the enriched environment treatment through all experiments until tested (older than 52 days age). Electrophysiological and Morris water maze testing was performed at 8 weeks of age. The results showed that prenatal stress impaired long-term potentiation (LTP) but facilitated long-term depression (LTD) in the hippocampal CA1 region in the slices. Furthermore, prenatal stress exacerbated the effects of acute stress on hippocampal LTP and LTD, and also impaired spatial learning and memory in the Morris water maze. However, all these deficits induced by prenatal stress were recovered by enriched environment treatment. This work observes a phenomenon that may contribute to the understanding of clinically important interactions among cognitive deficit, prenatal stress and enriched environment treatment. Enriched environment treatment on early postnatal periods may be one potentially important target for therapeutic interventions in preventing the prenatal stress-induced cognitive disorders.

Animals↗
PubMed2006

[Barrier function of esophagogastric junction in patients with gastroesophageal reflux disease].

OBJECTIVE: To investigate the barrier function of esophagogastric junction (EGJ) in the patients with gastroesophageal reflux diseases (GERD). METHODS: Ninety-six GERD patients and 18 healthy subjects (HSs) underwent esophageal manometry. Forty-two of the 96 patients were with reflux esophagitis (RE) and were divided into 2 subgroups according to the LA typing: 31 subgroup of LA-A or B (n = 31), and subgroup of LA-C or D (n = 11). Fifty-four of the 96 patients suffered from non-erosive reflux disease (NERD) and were divided into 2 subgroups based on 24 h esophageal pH monitoring: 31 patients with normal acid exposure (pH < 14.72 according to DeMeester scoring) and 23 with excessive acid exposure (pH > 14.72). The EGJ functions, including lower esophageal sphincter pressure (LESP), crura of diaphragm pressure (CDP), esophagogastric junction pressure (EGJP, sum of LESP and CDP), and post-lower esophageal sphincter relaxation pressure (post-LESRP), and the contractive pressure of esophageal body, including proximal esophageal contractive pressure (PECP) and distal esophageal contractive pressure (DECP), were measured. RESULTS: The levels of LESP, CDP, EGJP, and post-LESRP of the RE patients were (8 +/- 3), (13 +/- 7), (20 +/- 9), and (31 +/- 13) mm Hg respectively, all significantly lower than those of the NERD patients [(9 +/- 3), (18 +/- 6), (28 +/- 8), and (39 +/- 15) mm Hg, all P < 0.05]. The levels of LESP and post-LESRP of the NERD patients were significantly lower than those of the HSs [(32 +/- 7) and (50 +/- 15) mm Hg, both P < 0.05], however, the levels of CDP and EGJP of the NERD patients were both not significantly different from those of the HSs [(16 +/- 6) and (32 +/- 7) mm Hg, both P > 0.05]. The PECP and DECP of the RE and NERD patients were all significantly lower than those of the HSs (all P < 0.05), however, there were not significant differences in DECP and PECP between the RE and NERD patients (both P > 0.05). Among the NERD patients there were not significant differences in the PECP and DECP between the LA-A and B subgroup and RE LA-C and D subgroup, and among the NERD patients there were not significant differences in PECP and DECP between the subgroups with and without excessive esophageal acid exposure (all P > 0.05). CONCLUSION: The EGF anti-reflux function of the GERD patients is impaired. The function of crura of diaphragm of the NERD patients is almost normal, however, that of the RE patients is impaired. NERD and RE have different path physiological basis.

Adult↗
PubMed2006

Regulation of Ncx1 expression. Identification of regulatory elements mediating cardiac-specific expression and up-regulation.

The Na+-Ca2+ exchanger (NCX1) is up-regulated in hypertrophy and is often found up-regulated in end-stage heart failure. Studies have shown that the change in its expression contributes to contractile dysfunction. We have previously shown that the 1831-bp Ncx1 H1 (1831Ncx1) promoter directs cardiac-specific expression of the exchanger in both development and in the adult, and is sufficient for the up-regulation of Ncx1 in response to pressure overload. Here, we utilized adenoviral mediated gene transfer and transgenics to identify minimal regions and response elements that mediate Ncx1 expression in the heart. We demonstrate that the proximal 184 bp of the Ncx1 H1 (184Ncx1) promoter is sufficient for expression of reporter genes in adult cardiomyocytes and for the correct spatiotemporal pattern of Ncx1 expression in development but not for up-regulation in response to pressure overload. Mutational analysis revealed that both the -80 CArG and the -50 GATA elements were required for expression in isolated adult cardiomyocytes. Chromatin immunoprecipitation assays in adult cardiocytes demonstrate that SRF and GATA4 are associated with the proximal region of the endogenous Ncx1 promoter. Transgenic lines were established for the 1831Ncx1 promoter-luciferase containing mutations in the -80 CArG or -50 GATA element. No luciferase activity was detected during development, in the adult, or after pressure overload in any of the -80 CArG transgenic lines. The Ncx1 -50 GATA mutant promoter was sufficient for driving the normal spatiotemporal pattern of Ncx1 expression in development and for up-regulation in response to pressure overload but importantly, expression was no longer cardiac restricted. This work is the first in vivo study that demonstrates which cis elements are important for Ncx1 regulation.

Adenoviridae↗
PubMed2006

NR2B-containing N-methyl-D-aspartate subtype glutamate receptors regulate the acute stress effect on hippocampal long-term potentiation/long-term depression in vivo.

Behavioral stress facilitates long-term depression but impairs long-term potentiation in the hippocampus. Recent evidence in vitro demonstrates that the NR2B-containing N-methyl-D-aspartate subtype glutamate receptor antagonist Ro25-6981 prevents the behavioral stress-facilitated hippocampal long-term depression. It is, however, unknown whether Ro25-6981 influences hippocampal long-term depression and long-term potentiation induction in vivo under stressful condition. Here, we found that infusion of Ro25-6981 (2.3 microg in 6 microl, intracerebroventricular for 10 min) 30 min before low-frequency stimulation prevented the facilitation of hippocampal long-term depression by acute stress in anesthetized adult rats. Moreover, infusion of Ro25-6981 30 min before high-frequency stimulation reversed stress-impaired hippocampal long-term potentiation. These results suggest that the NR2B-containing N-methyl-D-aspartate subtype glutamate receptors are crucial for the effects of behavioral stress on hippocampal long-term depression and long-term potentiation in vivo.

Animals↗
PubMed2006

Ischemic postconditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway.

OBJECTIVE: We tested whether ischemic postconditioning (IPostC) is protective in remodeled myocardium. METHODS: Post-myocardial infarct (MI)-remodeled hearts after permanent coronary artery ligation and one kidney one clip (1K1C) hypertensive hearts of male Wistar rats were exposed to 40 min of ischemia followed by 90 min of reperfusion. IPostC was induced by six cycles of 10 s reperfusion interspersed by 10 s of no-flow ischemia. Activation of reperfusion injury salvage kinases was measured using Western blotting and in vitro kinase activity assays. RESULTS: IPostC prevented myocardial damage in both MI-remodeled and 1K1C hearts, as measured by decreased infarct size and lactate dehydrogenase release, and improved function. The reduction in infarct size and the recovery of left ventricular contractility achieved by IPostC was less in 1K1C hearts, but was unchanged in MI-remodeled hearts when compared to healthy hearts. In contrast, the recovery of inotropy was unaffected in 1K1C hearts, but was less in MI-remodeled hearts. Inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway with LY294002 abolished the protective effects of IPostC on both disease models and healthy hearts. Western blot analysis in conjunction with in vitro kinase activity assays identified protein kinase B (PKB)/Akt but not p42/p44 extracellular-signal regulated kinase 1/2 (ERK1/2) as the predominant kinase in IPostC-mediated cardioprotection in remodeled hearts. IPostC increased phosphorylation of the PKB/Akt downstream targets eNOS, GSK3beta, and p70S6K in remodeled hearts. CONCLUSION: Our results offer evidence that IPostC mediates cardioprotection in the remodeled rat myocardium primarily via activation of the PI3K-PKB/Akt reperfusion injury salvage kinase pathway.

Actins↗
PubMed2006

Enriched environment experience overcomes the memory deficits and depressive-like behavior induced by early life stress.

Stress in early life is believed to cause cognitive and affective disorders, and to disrupt hippocampal synaptic plasticity in adolescence into adult, but it is unclear whether exposure to enriched environment (EE) can overcome these effects. Here, we reported that housing rats in cages with limited nesting/bedding materials on postnatal days 2-21 reduced body weight gain, and this type of early life stress impaired spatial learning and memory of the Morris water maze and increased depressive-like behavior of the forced swim test in young adult rats (postnatal days 53-57). Early life stress also impaired long-term potentiation in hippocampal CA1 area of slices of young adult rats. Remarkably, EE experience on postnatal days 22-52 had no effect on spatial learning/memory and depressive-like behavior, but it significantly facilitated LTP in control rats, and completely overcame the effects of early life stress on young adult rats. These findings suggest that EE experience may be useful for clinical intervention in preventing cognitive and affective disorders during development.

Aging↗
PubMed2006

Morphine withdrawal modifies antinociceptive effects of acute morphine in rats.

Repeated opioid use is known to cause tolerance of antinociceptive effects. Whether opioid abstinence modifies antinociceptive effects is unknown. Here we reported that morphine withdrawal for 18 h and 4 days after repeated morphine treatment largely reduced tail-flick latencies compared with control, while the rats showed severe withdrawal syndromes. However, the latencies and withdrawal syndromes were restored to control level at 20 days withdrawal. Similarly, antinociceptive effects of acute morphine were decreased at 18 h and further decreased at 4 days but restored to control level at 20 days withdrawal. Behavioral stress that was given to the rats at 18 h withdrawal further reduced tail-flick latencies and antinociceptive effects. Conversely, the glucocorticoid receptor antagonist RU38486 increased tail-flick latencies and antinociceptive effects at 4 days withdrawal. These results suggest that morphine withdrawal could evoke behavioral stress to modify antinociceptive effects, implicating a significant influence of opioid abstinence on chronic pain treatment.

Analgesics, Opioid↗