The molecular mechanisms of genome reprogramming during transcriptional responses to stress are associated with specific chromatin modifications. Available data, however, describe histone modifications only at individual plant genes induced by stress. We have no knowledge of chromatin modifications taking place at genes whose transcription has been down-regulated or on the genome-wide chromatin modification patterns that occur during the plant's response to dehydration stress.

Eukaryotic translation initiation factor 3 subunit A (eIF3a) plays critical roles in regulating the initiation of protein translation, and eIF3a is highly expressed in lung cancer. In this study, we investigated the association of the positively selected SNPs of eIF3a with the response to and toxicity of platinum-based chemotherapy in Chinese patients with non-small cell lung cancer (NSCLC).

Alterations in embryonic neural stem cells play crucial roles in the pathogenesis of amyotrophic lateral sclerosis. We hypothesized that embryonic neural stem cells from SOD1(G93A) individuals might be more susceptible to oxidative injury, resulting in a propensity for neurodegeneration at later stages. In this study, embryonic neural stem cells obtained from human superoxide dismutase 1 mutant (SOD1(G93A)) and wild-type (SOD1(WT)) mouse models were exposed to H2O2. We assayed cell viability with mitochondrial succinic dehydrogenase colorimetric reagent, and measured cell apoptosis by flow cytometry. Moreover, we evaluated the expression of the adenosine monophosphate-activated protein kinase (AMPK) α-subunit, paired box 3 (Pax3) protein, and p53 in western blot analyses. Compared with SOD1(WT) cells, SOD1(G93A) embryonic neural stem cells were more likely to undergo H2O2-induced apoptosis. Phosphorylation of AMPKα in SOD1(G93A) cells was higher than that in SOD1(WT) cells. Pax3 expression was inversely correlated with the phosphorylation levels of AMPKα. p53 protein levels were also correlated with AMPKα phosphorylation levels. Compound C, an inhibitor of AMPKα, attenuated the effects of H2O2. These results suggest that embryonic neural stem cells from SOD1(G93A) mice are more susceptible to apoptosis in the presence of oxidative stress compared with those from wild-type controls, and the effects are mainly mediated by Pax3 and p53 in the AMPKα pathway.

We demonstrate through PdO doping that creation of heterojunctions on Co3O4 nanoparticles can quantitatively adjust band-gap and Fermi energy levels to study the impact of metal oxide nanoparticle semiconductor properties on cellular redox homeostasis and hazard potential. Flame spray pyrolysis (FSP) was used to synthesize a nanoparticle library in which the gradual increase in the PdO content (0-8.9%) allowed electron transfer from Co3O4 to PdO to align Fermi energy levels across the heterojunctions. This alignment was accompanied by free hole accumulation at the Co3O4 interface and production of hydroxyl radicals. Interestingly, there was no concomitant superoxide generation, which could reflect the hole dominance of a p-type semiconductor. Although the electron flux across the heterojunctions induced upward band bending, the E(c) levels of the doped particles showed energy overlap with the biological redox potential (BRP). This allows electron capture from the redox couples that maintain the BRP from -4.12 to -4.84 eV, causing disruption of cellular redox homeostasis and induction of oxidative stress. PdO/Co3O4 nanoparticles showed significant increases in cytotoxicity at 25, 50, 100, and 200 μg/mL, which was enhanced incrementally by PdO doping in BEAS-2B and RAW 264.7 cells. Oxidative stress presented as a tiered cellular response involving superoxide generation, glutathione depletion, cytokine production, and cytotoxicity in epithelial and macrophage cell lines. A progressive series of acute pro-inflammatory effects could also be seen in the lungs of animals exposed to incremental PdO-doped particles. All considered, generation of a combinatorial PdO/Co3O4 nanoparticle library with incremental heterojunction density allowed us to demonstrate the integrated role of E(v), E(c), and E(f) levels in the generation of oxidant injury and inflammation by the p-type semiconductor, Co3O4.

Copy number variation (CNV), a complex genomic rearrangement, has been extensively studied in humans and other organisms. In plants, CNVs of several genes were found to be responsible for various important traits; however, the cause and consequence of CNVs remains largely unknown. Recently released next-generation sequencing (NGS) data provide an opportunity for a genome-wide study of CNVs in rice.

To identify PAM50 subtype-specific associations between distant metastasis-free survival (DMFS) in breast cancer (BC) patients and gene modules describing potentially targetable oncogenic pathways, a comprehensive analysis evaluating the prognostic efficacy of published gene signatures in 2027 BC patients from 13 studies was conducted. We calculated 21 gene modules and computed hazard ratios (HRs) for DMFS for one-unit increases in module score, with and without adjustment for clinical characteristics. By comparing gene expression to survival outcomes, we derived four subtype-specific prognostic signatures for BC. Univariate and multivariate analyses showed that in the luminal A subgroup, E2F3, PTEN and GGI gene module scores were associated with clinical outcome. In the luminal B tumors, RAS was associated with DMFS and in the basal-like tumors, ER was associated with DMFS. Our defined gene modules predicted high-risk patients in multivariate analyses for the basal-like (HR: 2.19, p=2.5×10-4), luminal A (HR: 3.03, p=7.2×10-5), luminal B (HR: 3.00, p=2.4×10-10) and HER2+ (HR: 5.49, p=9.7×10-10) subgroups. We found that different modules are associated with DMFS in different BC subtypes. The results of this study could help to identify new therapeutic strategies for specific molecular subgroups of BC, and could enhance efforts to improve patient-specific therapy options.

The influenza pandemics have resulted in significant morbidity and mortality worldwide. Animal models are useful in the study of influenza virus pathogenesis. Because of various limitations in current laboratory animal models, it is essential to develop new alternative animal models for influenza virus research aimed at understanding the viral and host factors that contribute to virus infection in human.

PFTK1, also named Cyclin-Dependent Kinase 14 (CDK14), is a member of the cell division cycle 2 (CDC2)-related protein kinase family. It is a serine/threonine-protein kinase involved in the regulation of cell cycle progression and cell proliferation. In this study, we investigated the role of PFTK1 in epithelial ovarian cancer (EOC) development. The expression of PFTK1 was detected by Western blot and immunohistochemistry staining, both of which demonstrated that PFTK1 was overexpressed in EOC tissues and cells. Statistical analysis showed the expression of PFTK1 was associated with multiple clinicopathological factors, including tumor grade, FIGO stage, lymph node metastatis, Ki-67 expression and predicted a poor prognosis of EOC patients. With in vitro studies we found that PFTK1 expression was decreased in serum-starved ovarian cancer cells, and progressively increased after serum-re-feeding. Knocking PFTK1 down by small interfering RNA (siRNA) significantly inhibited ovarian cancer cell proliferation, migration and invasion. Taken together, our study suggested that PFTK1 played an important role in ovarian cancer development.

Multiple linear regression (MLR) and machine learning techniques in pharmacogenetic algorithm-based warfarin dosing have been reported. However, performances of these algorithms in racially diverse group have never been objectively evaluated and compared. In this literature-based study, we compared the performances of eight machine learning techniques with those of MLR in a large, racially-diverse cohort.

Schizophrenia is a complex and disabling psychiatric disorder, and tardive dyskinesia (TD) is a severe adverse drug effect occurring in 20% to 40% of schizophrenic patients chronically treated with typical neuroleptics. Previous studies suggested that the manganese superoxide dismutase (MnSOD) activity was associated with the development of schizophrenia. Ala-9Val polymorphism, a functional polymorphism of MnSOD gene, has been reported to be related to the risk of schizophrenia and TD. However, these studies did not lead to consistent results. We performed meta-analyses aiming to assess the association between MnSOD activity and schizophrenia, as well as the association of MnSOD Ala-9Val polymorphism with schizophrenia and TD in schizophrenic patients.We search for the literature on MnSOD and schizophrenia in English or Chinese published up to May 1, 2015 on PubMed, EMBASE, the Cochrane Databases, Chinese National Knowledge Infrastructure, China Biology Medical and Wanfang databases. Two investigators independently reviewed retrieved literature and evaluated eligibility. Discrepancy was resolved by consensus with a third reviewer. Data were pooled using fixed-effect or random-effect models. The standardized mean difference (SMD) and 95% confidence interval (CI) were calculated for the MnSOD activity. Pooled odds ratio (OR) and 95% CI were calculated for Ala-9Val genotype and allele frequencies.There were 6, 6, and 10 studies entering 3 parts of meta-analyses, respectively. The MnSOD activity of patients was significantly lower than that of controls (SMD = -0.94; 95% CI: -1.76, -0.12; P = 0.025). No significant associations of Ala-9Val genotypes (OR = 1.14; 95% CI: 0.97, 1.33; P = 0.109) and alleles (OR = 1.06; 95% CI: 0.94, 1.20; P = 0.361) with the risk of schizophrenia were observed. We also did not reveal significant associations of the genotypes (OR = 0.82; 95% CI: 0.66, 1.02; P = 0.075) and alleles (OR = 0.90; 95% CI: 0.76, 1.06; P = 0.215) with the risk of TD in schizophrenia.The decreased MnSOD activity may be associated with the risk of chronic schizophrenia in Chinese population, while MnSOD Ala-9Val polymorphism may not play a significant role in the development of schizophrenia and TD. Longitudinal studies with larger sample sizes and different ethnicities are needed to confirm the association of the MnSOD Ala-9Val variants with schizophrenia and TD.

Recent reports show that ER stress plays an important role in diabetic retinopathy (DR), but ER stress is a complicated process involving a network of signaling pathways and hundreds of factors, What factors involved in DR are not yet understood. We selected 89 ER stress factors from more than 200, A rat diabetes model was established by intraperitoneal injection of streptozotocin (STZ). The expression of 89 ER stress-related factors was found in the retinas of diabetic rats, at both 1- and 3-months after development of diabetes, by quantitative real-time polymerase chain reaction arrays. There were significant changes in expression levels of 13 and 12 ER stress-related factors in the diabetic rat retinas in the first and third month after the development of diabetes, Based on the array results, homocysteine- inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1(HERP), and synoviolin(HRD1) were studied further by immunofluorescence and Western blot. Immunofluorescence and Western blot analyses showed that the expression of HERP was reduced in the retinas of diabetic rats in first and third month. The expression of Hrd1 did not change significantly in the retinas of diabetic rats in the first month but was reduced in the third month.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and current treatments exhibit limited efficacy against advanced HCC. The majority of cancer-related deaths are caused by metastasis from the primary tumor, which indicates the importance of identifying clinical biomarkers for predicting metastasis and indicating prognosis. Patient-derived cells (PDCs) may be effective models for biomarker identification. In the present study, a wound healing assay was used to obtain 10 fast-migrated and 10 slow-migrated PDC cultures from 36 HCC samples. MicroRNA (miRNA) signatures in PDCs and PDC-derived exosomes were profiled by microRNA-sequencing. Differentially expressed miRNAs between the low- and fast-migrated groups were identified and further validated in 372 HCC profiles from The Cancer Genome Atlas (TCGA). Six exosomal miRNAs were identified to be differentially expressed between the two groups. In the fast-migrated group, five miRNAs (miR-140-3p, miR-30d-5p, miR-29b-3p, miR-130b-3p and miR-330-5p) were downregulated, and one miRNA (miR-296-3p) was upregulated compared with the slow-migrated group. Pathway analysis demonstrated that the target genes of the differentially expressed miRNAs were significantly enriched in the 'focal adhesion' pathway, which is consistent with the roles of these miRNAs in tumor metastasis. Three miRNAs, miR-30d, miR-140 and miR-29b, were significantly associated with patient survival. These findings indicated that these exosomal miRNAs may be candidate biomarkers for predicting HCC cell migration and prognosis and may guide the treatment of advanced HCC.

Reactive astrogliosis and early synaptic degeneration are 2 characteristic hallmarks in Alzheimer's disease (AD) brains, but a direct link between the 2 events has not been established. Here, we show that cancerous inhibitor of PP2A (CIP2A), a cancerous protein with high expression level in astrocytes, is upregulated in patients with AD and 3xTg-AD transgenic mice. Overexpression of CIP2A in astrocytes through adeno-associated virus infection both in cultured cells and in mice brains results in activation of astrocytes, increased production of cytokines and Aβ, and synaptic degeneration indicated by decreased levels of synaptic proteins, spine loss, and impairment in long-term potentiation. As a result of synaptic degeneration, CIP2A overexpression in astrocytes in vivo induces significant deficits in visual episodic memory detected by novel objective recognition test and spatial memory detected by Morris water maze. We conclude that CIP2A-promoted astrogliosis induces synaptic degeneration and cognitive deficits in AD.

Tribbles homolog 3 (TRIB3) mediating signaling pathways are closely related to blood pressure regulation. Our previous findings suggested a greater benefit on vascular outcomes in patients carrying TRIB3 (251, A > G, rs2295490) G allele with good glucose and blood pressure control. And TRIB3 (rs2295490) AG/GG genotypes were found to reduce primary vascular events in type 2 diabetic patients who received intensive glucose treatment as compared to those receiving standard glucose treatment. However, the effect of TRIB3 genetic variation on antihypertensives was not clear in essential hypertension patients. A total of 368 patients treated with conventional dosage of antihypertensives (6 groups, grouped by atenolol/bisoprolol, celiprolol, doxazosin, azelnidipine/nitrendipine, imidapril, and candesartan/irbesartan) were enrolled in our study. Genetic variations were successfully identified by sanger sequencing. A linear mixed model analysis was performed to evaluate blood pressures among TRIB3 (251, A > G) genotypes and adjusted for baseline age, gender, body mass index, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol and other biochemical factors appropriately. Our data suggested that TRIB3 (251, A > G) AA genotype carriers showed better antihypertensive effect than the AG/GG genotype carriers [P = 0.014 for DBP and P = 0.042 for mean arterial pressure (MAP)], with a maximal reduction of DBP by 4.2 mmHg and MAP by 3.56 mmHg after azelnidipine or nitrendipine treatment at the 4th week. Similar tendency of DBP-change and MAP-change was found for imidapril (ACEI) treatment, in which marginally significances were achieved (P = 0.073 and 0.075, respectively). Against that, we found that TRIB3 (251, A > G) AG/GG genotype carriers benefited from antihypertensive therapy of ARBs with a larger DBP-change during the period of observation (P = 0.036). Additionally, stratified analysis revealed an obvious difference of the maximal blood pressure change (13 mmHg for the MAP between male and female patients with AA genotype who took ARBs). Although no significant difference in antihypertensive effect between TRIB3 (251, A > G) genotypes in patients treated with α, β-ADRs was observed, we found significant difference in age-, sex-dependent manner related to α, β-ADRs. In conclusion, our data supported that TRIB3 (251, A > G) genetic polymorphism may serve as a useful biomarker in the treatment of hypertension.

The incidence of pancreatic neuroendocrine tumors (PNETs) is now increasing rapidly. The tumor grade of PNETs significantly affects the treatment strategy and prognosis. However, there is still no effective way to non-invasively classify PNET grades. Machine learning (ML) algorithms have shown potential in improving the prediction accuracy using comprehensive data.

Microglial activation and microglia-mediated inflammation play an important role in the occurrence, development, and outcome of stroke. Brain injury induces the activation and release of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin- (IL-) 1β, and IL-6. Many studies have confirmed that acupuncture is effective in treating ischemic stroke. However, its protective mechanism against ischemic brain injury is complex and multifactorial. In this study, we observed the effects of electroacupuncture at Baihui (GV20) and Dazhui (GV14) on microglial activation and inflammation in the cortical ischemic penumbra (IP) of permanent middle cerebral artery occlusion (pMCAO) rats. It was found that electroacupuncture inhibited the degeneration and necrosis of microglia in the cortical IP and ameliorated mitochondrial damage. Immunofluorescence and western blot analysis showed that microglia were in a resting state or weakly activated in the normal brain. After cerebral ischemia, the expression of microglial markers (Iba-1 and CD11b) increased, and NF-κB p65, IL-1β, and TNF-α expression gradually increased. The dynamic changes were generally temporally consistent. Electroacupuncture downregulated the expressions of Iba-1 and CD11b. Additionally, it inhibited the expression of NF-κB p65, IL-1β, and TNF-α and reduced the conversion of microglia to the M1 phenotype after ischemia. Electroacupuncture regulated the activation of microglia and microglia-mediated inflammation after cerebral ischemia, confirming the relevant theories regarding the effect of acupuncture treatment on cerebral ischemia and guiding clinical practice.

We aim to investigate the safety and efficacy of microwave ablation (MWA) combined with attenuated Salmonella typhimurium strain VNP20009 in treating hepatocellular carcinoma. Portions of tumor tissues were orthotopically implanted in the livers of 40 male rats weighed 150~200 g to establish tumor models. Three weeks later, the rats were randomly divided into four groups: (A) MWA plus VNP20009 group; (B) MWA group; (C) VNP20009 group; and (D) control group. Incomplete MWA was performed (20~30 W, 1~2 min) after the hepatic carcinoma was properly exposed. VNP20009 (about 1×107 cfu) was directly injected into the tumor immediately. MRI scans were performed to assess the tumor responses 7 and 14 days later, respectively. Micro CT was used to observe the lung metastases. After the animals were sacrificed or died, the tumors were cut off for the purpose of pathological and immunohistochemical analyses. The results showed that the mean tumor volumes of MWA plus VNP20009 group on the 7th and 14th day post treatment were obviously smaller than those of other groups (P < 0.05). Lung metastases rates were 20%, 60%, 30% and 100% in MWA plus VNP20009 group, MWA group, VNP20009 group and control group, respectively. The median survival of the rats in MWA plus VNP20009 group was distinctly longer than those in other groups (P < 0.05). In summary, MWA combined with VNP20009 produced better effects than MWA or VNP20009 alone in treating hepatic carcinoma. This strategy might have potential ability to decrease lung metastases and prolong the overall survival.

Colon cancer (CC) is a heterogeneous disease influenced by complex gene networks. As such, the relationship between networks and CC should be elucidated to obtain further insights into tumour biology.

Microtubules (MTs) are regulated by a number of known posttranslational modifications (PTMs) on α/β-tubulin to fulfill diverse cellular functions. Here, we showed that SUMOylation is a novel PTM on α-tubulin in vivo and in vitro. The SUMOylation on α-tubulin mainly occurred at Lys 96 (K96), K166, and K304 of soluble α-tubulin and could be removed by small ubiquitin-related modifier (SUMO)-specific peptidase 1. In vitro experiments showed that tubulin SUMOylation could reduce interprotofilament interaction, promote MT catastrophe, and impede MT polymerization. In cells, mutation of the SUMOylation sites on α-tubulin reduced catastrophe frequency and increased the proportion of polymerized α-tubulin, while upregulation of SUMOylation with fusion of SUMO1 reduced α-tubulin assembly into MTs. Additionally, overexpression of SUMOylation-deficient α-tubulin attenuated the neurite extension in Neuro-2a cells. Thus, SUMOylation on α-tubulin represents a new player in the regulation of MT properties.

The purpose of this meta-analysis was to compare the efficacy and safety of prone versus supine position ventilation for adult acute respiratory distress syndrome (ARDS) patients. The electronic databases of PubMed, Embase, and the Cochrane Library were systematically searched from their inception up to September 2020. The relative risks (RRs) and weighted mean differences (WMDs) with corresponding 95% confidence intervals (CIs) were employed to calculate pooled outcomes using the random-effects models. Twelve randomized controlled trials that had recruited a total of 2264 adults with ARDS were selected for the final meta-analysis. The risk of mortality in patients who received prone position ventilation was 13% lower than for those who received supine ventilation, but this effect was not statistically significant (RR: 0.87; 95% CI: 0.75-1.00; P = 0.055). There were no significant differences between prone and supine position ventilation on the duration of mechanical ventilation (WMD: -0.22; P = 0.883) or ICU stays (WMD: -0.39; P = 0.738). The pooled RRs indicate that patients who received prone position ventilation had increased incidence of pressure scores (RR: 1.23; P = 0.003), displacement of a thoracotomy tube (RR: 3.14; P = 0.047), and endotracheal tube obstruction (RR: 2.45; P = 0.001). The results indicated that prone positioning during ventilation might have a beneficial effect on mortality, though incidence of several adverse events was significantly increased for these patients.