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Energy restriction (ER) protects against cerebral ischemic injury, but the underlying mechanism remains largely unclear. Here, rats were fed ad libitum (AL) or on an alternate-day food deprivation intermittent fasting (IF) diet for 3 months, followed by middle cerebral artery occlusion (MCAO) surgery. The body weight, infarct volume, and neurological deficit score were accessed at the designated time points. ELISA, qRT-PCR, and Western blotting were used to determine cytokine secretion and the expression of SIRT6, TXNIP, and signaling molecules, respectively. Immunofluorescence evaluated microglial activation and angiogenesis in vivo. For in vitro study, oxygen-glucose deprivation/reoxygenation (OGD/R)-treated cell model was generated. MTT and tube formation assays were employed to determine cell viability and tube formation capability. ChIP assay detected chromatin occupancy of SIRT6 and SIRT6-mediated H3 deacetylation. We found that IF or ER mimetics ameliorated cerebral ischemic brain damage and microglial activation, and potentiated angiogenesis in vivo. ER mimetics or SIRT6 overexpression alleviated cerebral ischemia and reperfusion (I/R)-induced injury in vitro. SIRT6 suppressed TXNIP via deacetylation of H3K9ac and H3K56ac in HAPI cells and BMVECs. Downregulation of SIRT6 reversed ER mimetics-mediated protection during cerebral I/R in vitro. Our study demonstrated that ER-mediated upregulation of SIRT6 inhibited microglia activation and potentiated angiogenesis in cerebral ischemia via suppressing TXNIP.

Garlic (Allium sativum L.) is an important bulb vegetable with high culinary and medicinal values. It is cultivated by exclusively vegetative propagation which leads to complex virus infection, biodiversity reduction, inhibition of multiple breeding strategies. An efficient and widely applicable shoot regeneration system was established from garlic inflorescence as explant. By optimizing the basal medium type, pH value and explant size, a mean shoot regeneration rate of 97% and mean shoot number of 23.4 per explant were achieved in 14 commercial cultivars with various characteristics and origins. Histological observation revealed that shoots were regenerated through direct organogenesis when meristemoid initiated from subepidermal cells without callus formation followed by periclinal and anticlinal division of epidermal and subepidermal cells. No polymorphic bands were detected by simple sequence repeat (SSR) analysis between regenerants and donor plants. Furthermore, flow cytometry analysis indicated that there was no significant variability of genome size, and all plants maintained their ploidy. These results confirmed the clonal fidelity of regenerants. In conclusion, the present study provides a shoot regeneration system with great potential in micropropagation, germplasm preservation, genetic transformation and ploidy manipulation of garlic.Key messageOur study developed a widely applicable procedure for direct shoot regeneration via inflorescence of garlic and ascertained the clonal fidelity of regenerants by using simple sequence repeat (SSR) and flow cytometry.

[...]family screening was carried out with Sanger sequencing in all their patients and affected siblings. All patients were treated with three B vitamins (including mecobalamine: 0.5–1.5 mg/day, Folic acid tablets: 5–15 mg/day, Vitamin B6: 30–60 mg/day) once severe hyperhomocysteinemia (HHCY) is diagnosed. All seven patients had significantly increased plasma total Hcy (48–242 μmol/L) and decreased plasma levels of Vitamin B12 (below 50 pg/mL) and folic acid (below 1 ng/mL).

Background Post-radiation nasopharyngeal necrosis (PRNN) is a severe adverse event following re-radiotherapy for patients with locally recurrent nasopharyngeal carcinoma (LRNPC) and associated with decreased survival. Biological heterogeneity in recurrent tumors contributes to the different risks of PRNN. Radiomics can be used to mine high-throughput non-invasive image features to predict clinical outcomes and capture underlying biological functions. We aimed to develop a radiogenomic signature for the pre-treatment prediction of PRNN to guide re-radiotherapy in patients with LRNPC. Methods This multicenter study included 761 re-irradiated patients with LRNPC at four centers in NPC endemic area and divided them into training, internal validation, and external validation cohorts. We built a machine learning (random forest) radiomic signature based on the pre-treatment multiparametric magnetic resonance images for predicting PRNN following re-radiotherapy. We comprehensively assessed the performance of the radiomic signature. Transcriptomic sequencing and gene set enrichment analyses were conducted to identify the associated biological processes. Results The radiomic signature showed discrimination of 1-year PRNN in the training, internal validation, and external validation cohorts (area under the curve (AUC) 0.713–0.756). Stratified by a cutoff score of 0.735, patients with high-risk signature had higher incidences of PRNN than patients with low-risk signature (1-year PRNN rates 42.2–62.5% vs. 16.3–18.8%, P  < 0.001). The signature significantly outperformed the clinical model ( P  < 0.05) and was generalizable across different centers, imaging parameters, and patient subgroups. The radiomic signature had prognostic value concerning its correlation with PRNN-related deaths (hazard ratio (HR) 3.07–6.75, P  < 0.001) and all causes of deaths (HR 1.53–2.30, P  < 0.01). Radiogenomics analyses revealed associations between the radiomic signature and signaling pathways involved in tissue fibrosis and vascularity. Conclusions We present a radiomic signature for the individualized risk assessment of PRNN following re-radiotherapy, which may serve as a noninvasive radio-biomarker of radiation injury-associated processes and a useful clinical tool to personalize treatment recommendations for patients with LANPC.

In this study, the dispersion characteristics, impedance features, and absorption conditions of water-based electromagnetic (EM) absorbers are investigated. A methodology for the rapid construction of a three-layer water-based absorber structure is proposed. Concurrently, a weakly conditionally stable Hybrid Implicit-Explicit Finite Difference Time Domain (HIE-FDTD) method is introduced to enhance the computational efficiency of thin layer structures. Furthermore, the EM computation integrates thermal effect calculations. A hybrid approach, combining the HIE-FDTD and Finite Volume Method (FVM), is employed to analyze temperature variations induced by EM wave incidence on the absorber.

Aim： The efficacy of the Akt inhibitor perifosine against chronic myeloid leukemia （CML） cells and its mechanisms of action are unknown. In this study, the cytotoxic effects of perifosine on CML and acute myeloid leukemia （AML） cell lines were compared to elucidate the mechanisms underlying the differences. Methods： Human AML cell lines Kasumi-1 and HL-60, and the CML cell line K562 were used. Cell viability was quantitated using MTT assay. Apoptosis was determined using Annexin V-FITC/propidium iodide and Hoechst staining, which were followed by flow cytometry and fluorescence microscopy analysis, respectively. Caspase pathway activation and the expression of autophagy-related genes were examined using Western blot. Autophagy was studied using electron microscopy, the acridine orange staining method, and GFP-LC3 was examined with fluorescence microscopy. Results： In contrast to AML cell lines, the CML cell lines K562 and K562/G （an imatinib-insensitive CML cell line） were resistant to perifosine （2.5-20 μmol/L） in respect to inhibiting cell growth and inducing apoptosis. Perifosine （2.5, 5, and 10 μ/L） inhibited Akt and its phosphorylation in AML cells, but not in CML cells. Treatment with perifosine （20 μmol/L） resulted in autophagy in CML cells as shown by the increased formation of acidic vesicular organelles and the accumulation of LC3-11. Treatment of CML cells with perifosine （5, 10, and 20 μmol/L） dose-dependently upregulated AGT5, but not Beclin I at the protein level. Furthermore, inhibition of autophagy by chloroquine （40 nmol/L） significantly suppressed the cell growth and induced apoptosis in CML cells treated with perifosine （20 μmol/L）. Conclusion： Our results show that CML cell lines were resistant to the Akt inhibitor perifosine in vitro, which is due to perifosine-induced protective autophagy and upregulation of ATG5.

Aim： Plasminogen activator inhibitor-1 （PAl-1） is involved in the progression of pulmonary fibrosis. The present study was undertaken to examine the effects on pulmonary fibrosis of silencing PAl-1 expression with small interfering RNA （siRNA） and to assess the possible underlying mechanisms. Methods： Male Wistar rats were subjected to intratracheal injection of bleomycin （BLM, 5 mg/kg, 0.2 mL） to induce pulmonary fibrosis. Histopathological changes of lung tissue were examined with HE or Masson＇s trichrome staining. The expression levels of a-smooth muscle actin （a-SMA）, collagen type-I and type-Ⅲ, caspase-3, as well as p-ERK1/2 and PI3K/Akt in the lung tissue were evaluated using immunohistochemistry and Western blot analysis. The fibroblasts isolated from BLM-induced fibrotic lung tissue were cultured and transfected with pcDNA-PAI-1 or PAl-1 siRNA. The expression level of PAl-1 in the fibroblasts was measured using real time RT-PCR and Western blot analysis. The flbroblast proliferation was evaluated using MTr assay. Results： Intratracheal injection of PAl-1 siRNA （7.5 nmoL/O.2 mL） significantly alleviated alveolitis and collagen deposition, reduced the expression of PAl-l, α-SMA, collagen type-1 and collagen type-Ⅲ, and increased the expression of caspase-3 in BLM-induced fibrotic lung tissue. In consistence with the in vivo results, the proliferation of the cultured fibroblasts from BLM-induced fibrotic lung tissue was inhibited by transfection with PAl-1 siRNA, and accelerated by overexpression of PAl-1 by transfection with pcDNA-PAI-I. The expression of caspase-3 was increased as a result of PAl-1 siRNA transfection, and decreased after transfection with pcDNA-PAI-I. In addition, the levels of p-ERK1/2 and PI3K/Akt in the fibrogenic lungtissue were reduced after treatment with PAl-1 siRNA. Conclusion： The data demonstrate that PAl-1 siRNA inhibits alveolitis and pulmonary fibrosis in BLM-treated rats via inhibiting the proliferation and promoting the apoptosis of fibroblasts. Suppression ERK and AKT signalling pathways might have at least partly contrib- uted to this process. Targeting PAl-1 is a promising therapeutic strategy for pulmonary fibrosis.

Mutations of fins-like tyrosine kinase 3 （FLT3） and nucleophosmin （NPM1） exon 12 genes are the most common abnormalities in adult acute myeloid leukemia （AML） with normal cytogenetics. To assess the prognostic impact of the two gene mutations in Chinese AML patients, we used multiplex polymerase chain reaction （PCR） and capillary electrophoresis to screen 76 AML patients with normal cytogenetics for mutations in FLT3 internal tandem duplication （FLT3/ITD） and exon 12 of the NPM1 gene. FLT3/ITD mutation was detected in 15 （19.7%） of 76 subjects, and NPM1 mutation in 20 （26.3%） subjects. Seven （9.2%） cases were positive for both FLT3/ITD and NPM1 mutations Significantly more FLT3/ITD aberration was detected in subjects with French-American-British （FAB） M1 （42.8%）. NPM1 mutation was frequently detected in subjects with M5 （47.1%） and infrequently in subjects with M2 （11.1%）. FLT3 and NPM1 mutations were significantly associated with a higher white blood cell count in peripheral blood and a lower CD34 antigen expression, but not age, sex, or platelet count. Statistical analysis revealed that the FLT3/ITD- positive group had a lower complete remission （CR） rate （53.3% vs. 83.6%）. Survival analysis showed that the FLT3/ITD-positive/NPM1 mutation-negative group had worse overall survival （OS） and relapse-free survival （RFS）. The FLT3/ITD-positive/NPM1 mutation-positive group showed a trend towards favorable survival compared with the FLT3/ITD-positive/NPM1 mutation-negative group （P=0.069）. Our results indicate that the FLT3/ITD mutation might be a prognostic factor for an unfavorable outcome in Chinese AML subjects with normal cytogenetics, while NPM1 mutation may be a favorable prognostic factor for OS and RFS in the presence of FLT3/ITD.

The N-methyl-D-aspartate receptor （NMDAR） in adult forebrain is a heterotetramer mainly composed of two GIuN1 subunits and two GluN2A and/or GIuN2B subunits. The synaptic expression and relative numbers of GluN2A- and GluN2B-containing NMDARs play critical roles in controlling ca2＋-dependent signaling and synaptic plasticity. Previous studies have suggested that the synaptic trafficking of NMDAR subtypes is differentially regulated, but the precise molecular mechanism is not yet clear. In this study, we demonstrated that Bip, an endoplasmic reticulum （ER） chaperone, selectively interacted with GIuN2A and mediated the neuronal activity-induced assembly and synaptic incorporation of the GluN2A-containing NMDAR from dendritic ER. Furthermore, the GluN2A-specific synaptic trafficking was effectively disrupted by peptides interrupting the interaction between Bip and GIuN2A. Interesting- ly, fear conditioning in mice was disrupted by intraperitoneal injection of the interfering peptide before training. In summary, we have uncovered a novel mechanism for the activity-dependent supply of synaptic GluN2A-containing NMDARs, and demonstrated its relevance to memory formation.