Role of the RNA-Binding Protein Nrd1 in Stress Granule Formation and Its Implication in the Stress Response in Fission Yeast

We have previously identified the RNA recognition motif (RRM)-type RNA-binding protein Nrd1 as an important regulator of the posttranscriptional expression of myosin in fission yeast. Pmk1 MAPK-dependent phosphorylation negatively regulates the RNA-binding activity of Nrd1. Here, we report the role of Nrd1 in stress-induced RNA granules. Nrd1 can localize to poly(A)-binding protein (Pabp)-positive RNA granules in response to various stress stimuli, including heat shock, arsenite treatment, and oxidative stress. Interestingly, compared with the unphosphorylatable Nrd1, Nrd1DD (phosphorylation-mimic version of Nrd1) translocates more quickly from the cytoplasm to the stress granules in response to various stimuli; this suggests that the phosphorylation of Nrd1 by MAPK enhances its localization to stress-induced cytoplasmic granules. Nrd1 binds to Cpc2 (fission yeast RACK) in a phosphorylation-dependent manner and deletion of Cpc2 affects the formation of Nrd1-positive granules upon arsenite treatment. Moreover, the depletion of Nrd1 leads to a delay in Pabp-positive RNA granule formation, and overexpression of Nrd1 results in an increased size and number of Pabp-positive granules. Interestingly, Nrd1 deletion induced resistance to sustained stresses and enhanced sensitivity to transient stresses. In conclusion, our results indicate that Nrd1 plays a role in stress-induced granule formation, which affects stress resistance in fission yeast

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Long-term outcome of laminectomy and instrumented fusion for cervical ossification of the posterior longitudinal ligament

Between January 2000 and December 2003, a total of 83 patients (64 men and 19 women, average age: 56.4 years, range: 42–78 years) who underwent posterior laminectomy and instrumented fusion for ossification of the posterior longitudinal ligament (OPLL) were included in this study to investigate the long-term outcome of this surgical option and clarify which factors affect the prognosis. After an average 4.8-year follow-up, the mean Japanese Orthopaedic Association (JOA) score significantly increased from 9.2 ± 1.3 points before operation to 14.2 ±  0.9 points at the latest follow-up (P < 0.01). The improvement rate (IR) of neurological function ranged from 11.1 to 87.5%, with a mean of 62.4 ± 13.2%. Among 83 patients, 59 (71.1%) patients had a good prognosis (IR ≥ 50%), and the other 24 (28.9%) patients had a poor prognosis (IR < 50%). Postoperative nerve root palsy was the main complication in this series. Radiographic study showed that whilst improving cervical lordosis could provide a better decompression effect and good prognosis, it could have simultaneously contributed to the high incidence of postoperative nerve root palsy

Anterior corpectomy and fusion for severe ossification of posterior longitudinal ligament in the cervical spine

Between May 2002 and October 2006, 19 patients (17 men and 2 women; average age 57.2; range 47–71 years) received anterior corpectomy and fusion for severe ossification of the posterior longitudinal ligament (OPLL) in our department. Preoperative radiological evaluation showed the narrowing by the OPLL exceeded 50% in all cases, and OPLL extended from one to three vertebrae. We followed-up all patients for 12–36 months (mean 18 months). The Japanese Orthopaedic Association (JOA) score before surgery was 9.3 ± 1.8 (range 5–12) which significantly increased to 14.2 ± 1.3 (range 11–16) points at the last follow-up (P < 0.01). The improvement rate (IR) of neurological function ranged from 22.2–87.5%, with a mean of 63.2% ± 15.2%. The operation also provided a significant increase in the cervical lordosis and the cord flatting rate (P < 0.01). No severe neurological complication developed. We therefore concluded that anterior decompression and fusion was effective and safe in the treatment of the selected patients, although OPLL exceeded 50% diameter of the spinal canal