Human ELAV proteins are implicated in cell growth and differentiation via regulation of mRNA expression in the cytoplasm. In human embryonic teratocarcinoma (hNT2) cells transfected with the human neuronal ELAV-like protein, Hel-N1, neurites formed, yet cells were not terminally differentiated. Cells in which neurite formation was associated with Hel-N1 overexpression, also expressed increased levels of endogenous neurofilament M (NF-M) protein, which distributed along the neurites. However, steady-state levels of NF-M mRNA remained similar whether or not hNT2 cells were transfected with Hel-N1. These findings suggest that turnover of NF-M mRNA was not affected by Hel-N1 expression, despite the fact that Hel-N1 can bind to the 3 UTR of NF-M mRNA and was found directly associated with NF-M mRNA in transfected cells. Analysis of the association of NF-M mRNA with the translational apparatus in Hel-N1 transfectants showed nearly complete recruitment to heavy polysomes, indicating that Hel-N1 caused an increase in translational initiation. Our results suggest that the stability and/or translation of ARE-containing mRNAs can be regulated independently by the ELAV protein, Hel-N1, depending upon sequence elements in the 3 UTRs and upon the inherent turnover rates of the mRNAs that are bound to Hel-N1 in vivo.
Disruption of mitotic events contributes greatly to genomic instability and results in mutator phenotypes. Indeed, abnormalities of mitotic components are closely associated with malignant transformation and tumorigenesis. Here we show that ninein-like protein (Nlp), a recently identified BRCA1-associated centrosomal protein involved in microtubule nucleation and spindle formation, is an oncogenic protein. Nlp was found to be overexpressed in approximately 80% of human breast and lung carcinomas analyzed. In human lung cancers, this deregulated expression was associated with NLP gene amplification. Further analysis revealed that Nlp exhibited strong oncogenic properties; for example, it conferred to NIH3T3 rodent fibroblasts the capacity for anchorage-independent growth in vitro and tumor formation in nude mice. Consistent with these data, transgenic mice overexpressing Nlp displayed spontaneous tumorigenesis in the breast, ovary, and testicle within 60 weeks. In addition, Nlp overexpression induced more rapid onset of radiation-induced lymphoma. Furthermore, mouse embryonic fibroblasts (MEFs) derived from Nlp transgenic mice showed centrosome amplification, suggesting that Nlp overexpression mimics BRCA1 loss. These findings demonstrate that Nlp abnormalities may contribute to genomic instability and tumorigenesis and suggest that Nlp might serve as a potential biomarker for clinical diagnosis and therapeutic target.
Severe sepsis has a high fatality rate, but no clinical indices for prognosis have been established. In recent years, the renin-angiotensin system (RAS) has received considerable attention. However, clinical data on RAS are inconsistent. Therefore, the aim of the present study was to assess the significance of RAS in the prognosis of sepsis. Blood samples were collected from patients, who met the diagnostic criteria of severe sepsis, on day 1 (D1) and 3 (D3). For each sample, the levels of angiotensin II (AngII), angiotensin-converting enzyme (ACE) and additional indices were measured. Patients were monitored for 28 days. On the D1 of inclusion, the average Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 22.2 and the Sepsis-related Organ Failure Assessment (SOFA) score was 6.1. Logistic regression analysis revealed that mortality-associated variables included the APACHE II score on D1, the SOFA score on D1, high lactic acid levels on D3 and low AngII and ACE levels on D1 and D3. AngII levels (<86.1 ng/ml) on D1 had a sensitivity of 88.2% and specificity of 77.3% for predicting mortality. ACE levels (<39.2 ng/ml) on D1 had a sensitivity of 88.2% and specificity of 72.7% for predicting mortality. These two indices were better than the APACHE II and SOFA scores. Therefore, low expression levels of AngII and ACE are valuable in predicting the mortality of patients with severe sepsis.
Purpose. To evaluate the corneal aberration changes in dry eye patients after treatment with artificial eye drops. Methods. Thirty mild to moderate dry eye patients treated with artificial eye drops and twenty comparable dry eye patients were recruited as controls. Anterior corneal aberrations over 3 mm and 5 mm analytical zones including total, 3rd to 5th high order aberrations (HOAs), spherical aberration (SA), and vertical (V-coma) and horizontal coma (H-coma) obtained from corneal topography data at baseline and 2 weeks after treatment were evaluated. Results. For 3 mm zone, trefoils, V-coma, H-coma terms, and 3rd and 5th HOAs were significantly decreased (p < 0.05) in the treatment group. For 5 mm zone, instillation of eye drops reduced H-coma, SA terms, 3rd to 5th orders, and total HOAs all showed a significant decrease (p < 0.05). The root mean square analysis of the Zernike terms also showed similar statistical results. For control group, all individual terms and total HOAs did not have significant changes over 3 mm and 5 mm zones (p > 0.05). Conclusions. Treatment with artificial eye drops can effectively improve the corneal optical quality of dry eye patients by ameliorating the HOAs of anterior corneal surface.
Summary
DM catalyses class II‐associated invariant chain peptide (CLIP) release, edits the repertoire of peptides bound to major histocompatibility complex (MHC) class II molecules, affects class II structure, and thereby modulates binding of conformation‐sensitive anti‐class II antibodies. Here, we investigate the ability of DM to enhance the cell surface binding of monomorphic antibodies. We show that this enhancement reflects increases in cell surface class II expression and total cellular abundance, but notably these effects are selective for particular alleles. Evidence from analysis of cellular class II levels after cycloheximide treatment and from pulse‐chase experiments indicates that DM increases the half‐life of affected alleles. Unexpectedly, the pulse‐chase experiments also revealed an early effect of DM on assembly of these alleles. The allelically variant feature that correlates with susceptibility to these DM effects is low affinity for CLIP; DM‐dependent changes in abundance are reduced by invariant chain (CLIP) mutants that enhance CLIP binding to class II. We found evidence that DM mediates rescue of peptide‐receptive molecules from inactive forms in vitro and evidence suggesting that a similar process occurs in cells. Thus, multiple mechanisms, operating along the biosynthetic pathway of class II molecules, contribute to DM‐mediated increases in the abundance of low‐CLIP‐affinity alleles.
There is a high incidence of new T2DM at 8% over 4 years among Chinese. Larger BMI, higher glucose levels, and lower levels of ApoA1 are significantly and independently associated with new T2DM. Lower ApoA1 improves the risk prediction of new type 2 diabetes when it was added to the existing risk models.
Background
Platinum-based chemotherapy is a mainstay for treating esophageal cancer patients. In this manuscript, we have provided clues for influence of platinum on overall m6A level and further investigated the potential regulatory mechanism.
Methods
qRT-PCR was used to measure SNHG3 and miR-186-5p expression; ELISA and western blot were used to measure the expression of METTL3. CCK8 was used to measure the cell proliferation rate. Caspase 3/7 activity was used to measure the apoptosis rate. Dual luciferase reporter gene assay and RNA pull down assay were used to investigate the potential crosstalk between miR-186-5p and SNHG3; and miR-186-5p and METTL3.
Results
m6A level was increased when treated with platinum (CDDP, CPB and L-OHP). Besides, SNHG3 expression was induced and miR-186-5p expression was suppressed by platinum. Furthermore, SNHG3 could promote the m6A level, however miR-186-5p inhibited the m6A level through targeting METTL3. SNHG3 interacts with miR-186-5p to negatively regulate the expression of miR-186-5p; and miR-186-5p might bind to the 3′UTR of METTL3 to regulate its expression.
Conclusion
Platinum can increase the overall m6A level of esophageal cancer. SNHG3/miR-186-5p, induced by platinum, was involved in regulating m6A level by targeting METTL3. Our manuscript has provided clues that regulating m6A level might be a novel way to enhance the platinum efficacy.
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