SUVH1, a Su(var)3-9 family member, promotes the expression of genes targeted by DNA methylation.

Transposable elements are found throughout the genomes of all organisms. Repressive marks such as DNA methylation and histone H3 lysine 9 (H3K9) methylation silence these elements and maintain genome integrity. However, how silencing mechanisms are themselves regulated to avoid the silencing of genes remains unclear. Here, an anti-silencing factor was identified using a forward genetic screen on a reporter line that harbors a LUCIFERASE (LUC) gene driven by a promoter that undergoes DNA methylation. SUVH1, a Su(var)3-9 homolog, was identified as a factor promoting the expression of the LUC gene. Treatment with a cytosine methylation inhibitor completely suppressed the LUC expression defects of suvh1, indicating that SUVH1 is dispensable for LUC expression in the absence of DNA methylation. SUVH1 also promotes the expression of several endogenous genes with promoter DNA methylation. However, the suvh1 mutation did not alter DNA methylation levels at the LUC transgene or on a genome-wide scale; thus, SUVH1 functions downstream of DNA methylation. Histone H3 lysine 4 (H3K4) trimethylation was reduced in suvh1; in contrast, H3K9 methylation levels remained unchanged. This work has uncovered a novel, anti-silencing function for a member of the Su(var)3-9 family that has previously been associated with silencing through H3K9 methylation

Dynamical analysis of fractional-order Mathieu equation

The dynamical characteristics of Mathieu equation with fractional-order derivative is analytically studied by the Lindstedt-Poincare method and the multiple-scale method. The stability boundaries and the corresponding periodic solutions on these boundaries for the constant stiffness δ0=n2 (n = 0, 1, 2, …), are analytically obtained. The effects of the fractional-order parameters on the stability boundaries and the corresponding periodic solutions, including the fractional coefficient and the fractional order, are characterized by the equivalent linear damping coefficient (ELDC) and the equivalent linear stiffness coefficient (ELSC). The comparisons between the transition curves on the boundaries obtained by the approximate analytical solution and the numerical method verify the correctness and satisfactory precision of the analytical solution. The following analysis is focused on the effects of the fractional parameters on the stability boundaries located in the δ-ε plane. It is found that the increase of the fractional order p could make the ELDC larger and ELSC smaller, which could result into the rightwards and upwards moving of the stability boundaries simultaneously. It could also be concluded the increase of the fractional coefficient K1 would make the ELDC and ELSC larger, which could move the transition curves to the left and upwards at the same time. These results are very helpful to design, analyze or control this kind of system, and could present beneficial reference to the similar fractional-order system

The MBD7 complex promotes expression of methylated transgenes without significantly altering their methylation status.

DNA methylation is associated with gene silencing in eukaryotic organisms. Although pathways controlling the establishment, maintenance and removal of DNA methylation are known, relatively little is understood about how DNA methylation influences gene expression. Here we identified a METHYL-CpG-BINDING DOMAIN 7 (MBD7) complex in Arabidopsis thaliana that suppresses the transcriptional silencing of two LUCIFERASE (LUC) reporters via a mechanism that is largely downstream of DNA methylation. Although mutations in components of the MBD7 complex resulted in modest increases in DNA methylation concomitant with decreased LUC expression, we found that these hyper-methylation and gene expression phenotypes can be genetically uncoupled. This finding, along with genome-wide profiling experiments showing minimal changes in DNA methylation upon disruption of the MBD7 complex, places the MBD7 complex amongst a small number of factors acting downstream of DNA methylation. This complex, however, is unique as it functions to suppress, rather than enforce, DNA methylation-mediated gene silencing

Detection of Pol IV/RDR2-Dependent Transcripts at the Genomic Scale in \u3cem\u3eArabidopsis\u3c/em\u3e Reveals Features and Regulation of siRNA Biogenesis

Twenty-four-nucleotide small interfering (si)RNAs are central players in RNA-directed DNA methylation (RdDM), a process that establishes and maintains DNA methylation at transposable elements to ensure genome stability in plants. The plant-specific RNA polymerase IV (Pol IV) is required for siRNA biogenesis and is believed to transcribe RdDM loci to produce primary transcripts that are converted to double-stranded RNAs (dsRNAs) by RDR2 to serve as siRNA precursors. Yet, no such siRNA precursor transcripts have ever been reported. Here, through genome-wide profiling of RNAs in genotypes that compromise the processing of siRNA precursors, we were able to identify Pol IV/RDR2-dependent transcripts from tens of thousands of loci. We show that Pol IV/RDR2-dependent transcripts correspond to both DNA strands, whereas the RNA polymerase II (Pol II)-dependent transcripts produced upon derepression of the loci are derived primarily from one strand. We also show that Pol IV/RDR2-dependent transcripts have a 5′ monophosphate, lack a poly(A) tail at the 3′ end, and contain no introns; these features distinguish them from Pol II-dependent transcripts. Like Pol II-transcribed genic regions, Pol IV-transcribed regions are flanked by A/T-rich sequences depleted in nucleosomes, which highlights similarities in Pol II- and Pol IV-mediated transcription. Computational analysis of siRNA abundance from various mutants reveals differences in the regulation of siRNA biogenesis at two types of loci that undergo CHH methylation via two different DNA methyltransferases. These findings begin to reveal features of Pol IV/RDR2-mediated transcription at the heart of genome stability in plants

Serum cytokines and neutrophil-to-lymphocyte ratio as predictive biomarkers of benefit from PD-1 inhibitors in gastric cancer

BackgroundImmunotherapy is significantly revolutionizing cancer treatment and demonstrating promising efficacy in gastric cancer (GC) patients. However, only a subset of patients could derive benefits from targeted monoclonal antibody therapy against programmed death receptor 1 (PD-1). This study aims to identify suitable serum cytokines and blood cell ratios as predictive biomarkers to aid in the selection of GC patients likely to benefit from PD-1 inhibitors.Materials and methodsThis retrospective study included 41 GC patients who received PD-1 inhibitors combined with chemotherapy, 36 GC patients treated solely with chemotherapy, and 33 healthy controls. The study assessed the levels of seven cytokines: interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-17A, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and various inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR), total lymphocyte count (TLC), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR). Measurements were obtained using the inpatient system. Univariate and multivariate Cox regression analyses were performed to evaluate the predictive significance of these hematologic parameters for clinical outcomes.ResultsLevels of IL-6, IL-10, TNF-α, NLR, and PLR were significantly elevated in GC patients compared to healthy controls, while TLC and LMR were higher in the control group. Among the 41 patients receiving PD-1 inhibitors and chemotherapy, baseline IL-2 was associated with OS and PFS. Additionally, IL-6 and IL-17A correlated with OS, while NLR was linked to PFS (all P<0.05). These factors were identified as independent prognostic indicators in both univariate and multivariate analyses. Furthermore, almost all cytokine levels increased following the initiation of PD-1 inhibitor treatment.ConclusionsThe introduction of PD-1 inhibitors alongside chemotherapy in GC impacts serum cytokine levels. IL-2, IL-6, IL-17A, and NLR exhibit potential as reliable circulating predictive biomarkers for identifying patients who may benefit from PD-1 inhibitors combined with chemotherapy

DNA Topoisomerase 1α Promotes Transcriptional Silencing of Transposable Elements through DNA Methylation and Histone Lysine 9 Dimethylation in Arabidopsis

RNA-directed DNA methylation (RdDM) and histone H3K9 dimethylation (H3K9me2) are related transcriptional silencing mechanisms that target transposable elements (TEs) and repeats to maintain genome stability in plants. RdDM is mediated by small and long noncoding RNAs produced by the plant-specific RNA polymerases Pol IV and Pol V, respectively. Through a chemical genetics screen with a luciferase-based DNA methylation reporter, LUCL, we found that camptothecin, a compound with anti- cancer properties that targets DNA topoisomerase 1α (TOP1α) was able to de-repress LUCL by reducing its DNA methylation and H3K9me2 levels. Further studies with Arabidopsis top1α mutants showed that TOP1α silences endogenous RdDM loci by facilitating the production of Pol V-dependent long non-coding RNAs, AGONAUTE4 recruitment and H3K9me2 deposition at TEs and repeats. This study assigned a new role in epigenetic silencing to an enzyme that affects DNA topology.Fil: Dinh, Thanh Theresa. University of California Riverside. Center for Plant Cell Biology, Institute of Integrative Genome Biology, Department of Botany and Plant Sciences; Estados Unidos. University of California Riverside. Center for Plant Cell Biology, Institute of Integrative Genome Biology. ChemGen IGERT program; Estados UnidosFil: Gao, Lei. University of California Riverside. Center for Plant Cell Biology, Institute of Integrative Genome Biology, Department of Botany and Plant Sciences; Estados UnidosFil: Liu, Xigang . University of California Riverside. Center for Plant Cell Biology, Institute of Integrative Genome Biology, Department of Botany and Plant Sciences; Estados UnidosFil: Li, Dongming. University of California Riverside. Center for Plant Cell Biology, Institute of Integrative Genome Biology, Department of Botany and Plant Sciences; Estados Unidos. Lanzhou University. School of Life Sciences Plant Biology Laboratory; ChinaFil: Li, Shengben. University of California Riverside. Center for Plant Cell Biology, Institute of Integrative Genome Biology, Department of Botany and Plant Sciences; Estados UnidosFil: Zhao, Yuanyuan. University of California Riverside. Center for Plant Cell Biology, Institute of Integrative Genome Biology, Department of Botany and Plant Sciences; Estados UnidosFil: O'leary, Michael. University of California Riverside. Center for Plant Cell Biology, Institute of Integrative Genome Biology, Department of Botany and Plant Sciences; Estados UnidosFil: Le, Brandon. University of California Riverside. Center for Plant Cell Biology, Institute of Integrative Genome Biology, Department of Botany and Plant Sciences; Estados UnidosFil: Schmitz, Robert J.. The Salk Institute for Biological Studies. Plant Biology Laboratory; Estados UnidosFil: Manavella, Pablo Andrés. Max Planck Institute for Developmental Biology. Department of Molecular Biology; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Santa Fe. Instituto de Agrobiotecnologia del Litoral; ArgentinaFil: Li, Shaofang. University of California Riverside. Center for Plant Cell Biology, Institute of Integrative Genome Biology, Department of Botany and Plant Sciences; Estados UnidosFil: Weigel, Detlef. Max Planck Institute for Developmental Biology. Department of Molecular Biology; AlemaniaFil: Pontes, Olga. University of New Mexico. Department of Biology; Estados UnidosFil: Ecker, Joseph R.. The Salk Institute for Biological Studies. Howard Hughes Medical Institute; Estados Unidos. The Salk Institute for Biological Studies. Plant Biology Laboratory; Estados UnidosFil: Chen, Xuemei. University of California Riverside. Center for Plant Cell Biology, Institute of Integrative Genome Biology, Department of Botany and Plant Sciences; Estados Unidos. University of California Riverside. Howard Hughes Medical Institute, ; Estados Unido

Arabidopsis AAR2, a conserved splicing factor in eukaryotes, acts in microRNA biogenesis

MicroRNAs (miRNAs) play an essential role in plant growth and development, and as such, their biogenesis is fine-tuned via regulation of the core microprocessor components. Here, we report that Arabidopsis AAR2, a homolog of a U5 snRNP assembly factor in yeast and humans, not only acts in splicing but also promotes miRNA biogenesis. AAR2 interacts with the microprocessor component hyponastic leaves 1 (HYL1) in the cytoplasm, nucleus, and dicing bodies. In aar2 mutants, abundance of nonphosphorylated HYL1, the active form of HYL1, and the number of HYL1-labeled dicing bodies are reduced. Primary miRNA (pri-miRNA) accumulation is compromised despite normal promoter activities of MIR genes in aar2 mutants. RNA decay assays show that the aar2-1 mutation leads to faster degradation of pri-miRNAs in a HYL1-dependent manner, which reveals a previously unknown and negative role of HYL1 in miRNA biogenesis. Taken together, our findings reveal a dual role of AAR2 in miRNA biogenesis and pre-messenger RNA splicing.Fil: Fan, Lusheng. University of California; Estados UnidosFil: Gao, Bin. University of California; Estados UnidosFil: Xu, Ye. University of California; Estados UnidosFil: Flynn, Nora. University of California; Estados UnidosFil: Le, Brandon. University of California; Estados UnidosFil: You, Chenjiang. Fudan University; ChinaFil: Li, Shaofang. Fudan University; ChinaFil: Achkar, Natalia Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Agrobiotecnología del Litoral. Universidad Nacional del Litoral. Instituto de Agrobiotecnología del Litoral; ArgentinaFil: Manavella, Pablo Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Agrobiotecnología del Litoral. Universidad Nacional del Litoral. Instituto de Agrobiotecnología del Litoral; ArgentinaFil: Yang, Zhenbiao. University of California; Estados UnidosFil: Chen, Xuemei. University of California; Estados Unido

The effect of argatroban on early neurological deterioration and outcomes in minor ischemic stroke: preliminary findings

BackgroundMinor ischemic stroke (MIS) is associated with early neurological deterioration (END) and poor prognosis. Here, we investigated whether argatroban administration can mitigate MIS-associated END and improve functional outcomes by monitoring activated partial thrombin time (APTT).MethodsData were collected for patients with MIS admitted to our hospital from January 2019 to December 2022. Patients were divided into a dual antiplatelet therapy (DAPT) group (aspirin + clopidogrel) and an argatroban group (aspirin + argatroban). Those in the latter group who achieved a target APTT of 1.5–3-fold that of baseline and <100 s at 2 h after argatroban infusion were included in the argatroban subgroup. The primary outcome was the END rate of the DAPT group versus that of the argatroban group or the argatroban subgroup. Secondary outcomes included the proportion of patients with modified Rankin Scale (mRS) 0–2 at 7 and 90 days. In addition, baseline date were compared between patients with and without END in the argatroban group.Results363 patients were included in the DAPT group and 270 in the argatroban group. There were no significant differences in any above outcome between them. 207 pairs were included in the DAPT group and the argatroban subgroup after 1:1 propensity score matching (PSM). Significant differences were observed in the proportion of END (OR, 2.337; 95% CI, 1.200–4.550, p = 0.011) and mRS 0–2 at 7 days (OR, 0.624; 95% CI, 0.415–0.939, p = 0.023), but not in mRS 0–2 at 90 days or the hemorrhagic events between the two groups. In the argatroban group, univariate analysis showed that the rate of diabetes (OR, 2.316; 95% CI, 1.107–4.482, p = 0.023), initial random blood glucose (OR, 1.235; 95% CI, 1.070–1.425, p = 0.004), drinking history (OR, 0.445; 95% CI, 0.210–0.940, p = 0.031) or those reaching the target APTT (OR, 0.418; 95% CI, 0.184–0.949, p = 0.033) was significantly different among patients with and without END. However, there were no statistical differences in these parameters between them following multivariate analysis.ConclusionIn patients with MIS, argatroban administration and reaching the target APTT can reduce the incidence of END and improve short-term functional prognosis