A first comprehensive analysis of Transcribed Ultra Conserved Regions uncovers important regulatory functions of novel non-coding transcripts in gliomas.

Transcribed Ultra-Conserved Regions (TUCRs) represent a severely understudied class of putative non-coding RNAs (ncRNAs) that are 100% conserved across multiple species. We performed the first-ever analysis of TUCRs in glioblastoma (GBM) and low-grade gliomas (LGG). We leveraged large human datasets to identify the genomic locations, chromatin accessibility, transcription, differential expression, correlation with survival, and predicted functions of all 481 TUCRs, and identified TUCRs that are relevant to glioma biology. Of these, we investigated the expression, function, and mechanism of action of the most highly upregulated intergenic TUCR, uc.110, identifying it as a new oncogene. Uc.110 was highly overexpressed in GBM and LGG, where it promoted malignancy and tumor growth. Uc.110 activated the WNT pathway by upregulating the expression of membrane frizzled-related protein (MFRP), by sponging the tumor suppressor microRNA miR-544. This pioneering study shows important roles for TUCRs in gliomas and provides an extensive database and novel methods for future TUCR research.

A first comprehensive analysis of Transcribed Ultra Conserved Regions uncovers important regulatory functions of novel non-coding transcripts in gliomas.

Transcribed Ultra-Conserved Regions (TUCRs) represent a severely understudied class of putative non-coding RNAs (ncRNAs) that are 100% conserved across multiple species. We performed the first-ever analysis of TUCRs in glioblastoma (GBM) and low-grade gliomas (LGG). We leveraged large human datasets to identify the genomic locations, chromatin accessibility, transcription, differential expression, correlation with survival, and predicted functions of all 481 TUCRs, and identified TUCRs that are relevant to glioma biology. Of these, we investigated the expression, function, and mechanism of action of the most highly upregulated intergenic TUCR, uc.110, identifying it as a new oncogene. Uc.110 was highly overexpressed in GBM and LGG, where it promoted malignancy and tumor growth. Uc.110 activated the WNT pathway by upregulating the expression of membrane frizzled-related protein (MFRP), by sponging the tumor suppressor microRNA miR-544. This pioneering study shows important roles for TUCRs in gliomas and provides an extensive database and novel methods for future TUCR research.

Expression of programmed death ligand-1 (PD-L1) and tumor infiltrating lymphocytes (TILs) in breast carcinoma and their clinical significance.

Background and Aim: Carcinoma of the breast is the second most common cause of cancer death in women. Expression of programmed death ligand-1 (PD-L1) in cancer cells plays an important role in tailored therapy. This can be evaluated by immunohistochemistry using a monoclonal PD-L1 antibody in formalin-fixed and paraffin-embedded (FFPE) specimens. Our aim was to evaluate the expression of PD-L1 and tumor infiltrating lymphocytes (TILs) in invasive carcinoma of breast and their clinicopathological correlation. Materials and Methods: Immunohistochemical staining for PD-L1 and TILs was done in paraffin-embedded tissues of histologically diagnosed 50 cases of breast carcinoma. Statistical analysis was done using Statistical Package for the Social Sciences (SPSS) 22 software. Results: Out of these 50 cases, PD-L1 and TIL expression were seen in 16 (32%) cases and 18 (36%) cases, respectively. PD-L1 positivity was seen in 33.33% cases of grade 1 breast carcinoma, 13.79% of cases of grade 2 breast carcinoma, and in 75% case of grade 3 breast carcinoma. TILs showed positivity in 6.9% cases of grade 1 breast carcinoma, 13.79% of cases of grade 2 breast carcinoma, and in 100% cases of grade 3 breast carcinoma. Proportion of patients having PD-L1 expression was higher in grade 3 carcinoma than in grade 1 or 2. The differences were statistically significant (Chi-square value = 13.417, degree of freedom = 1, P < 0.05). The Chi-square value for TILs was 28.07, degree of freedom was 1, and P value was <0.05, which was statistically significant. Conclusion: Both PD-L1 and TILs showed maximum positivity in grade 3 breast carcinoma.

Analysis of the interaction of a non-canonical twin half-site of Cyclic AMP-Response Element (CRE) with CRE-binding protein.

Differential regulation of a gene having either canonical or non-canonical cyclic AMP response element (CRE) in its promoter is primarily accomplished by its interactions with CREB (cAMP-response element binding protein). The present study aims to delineate the mechanism of the CREB-CRE interactions at the Oncostatin-M (osm) promoter by in vitro and in silico approaches. The non-canonical CREosm consists of two half-CREs separated by a short intervening sequence of 9 base pairs. In this study, in vitro binding assays revealed that out of the two CRE half-sites, the right half-CRE was indispensable for binding of CREB, while the left sequence showed weaker binding ability and specificity. Genome-wide modeling and high throughput free energy calculations for the energy-minimized models containing CREB-CREosm revealed that there was no difference in the binding of CREB to the right half of CREosm site when compared to the entire CREosm. These results were in accordance with the in vitro studies, confirming the indispensable role of the right half-CREosm site in stable complex formation with the CREB protein. Additionally, conversion of the right half-CREosm site to a canonical CRE palindrome showed stronger CREB binding, irrespective of the presence or absence of the left CRE sequence. Thus, the present study establishes an interesting insight into the interaction of CREB with a CRE variant located at the far end of a TATA-less promoter of a cytokine-encoding gene, which in turn could be involved in the regulation of transcription under specific conditions.

Transcribed Ultraconserved Regions in Cancer.

Transcribed ultraconserved regions are putative lncRNA molecules that are transcribed from DNA that is 100% conserved in human, mouse, and rat genomes. This is notable, as lncRNAs are typically poorly conserved. TUCRs remain very understudied in many diseases, including cancer. In this review, we summarize the current literature on TUCRs in cancer with respect to expression deregulation, functional roles, mechanisms of action, and clinical perspectives.

Road Traffic Injuries: A Study on Severity and Outcome among Inpatients of a Tertiary Care Level Hospital of West Bengal, India.

BACKGROUND: Road traffic injuries (RTIs) are a complex phenomenon caused by nonlinear combination and interaction of man, vehicles, road, and environment. AIM: This study aims to find out the outcome and severity of RTI in a district of West Bengal, India. SETTINGS AND DESIGN: A cross-sectional study was conducted among inpatients of Departments of Surgery and Orthopedics of Bankura Sammilani Medical College and Hospital, West Bengal, India. MATERIALS AND METHODS: The study was conducted for 1 year interviewing 295 RTI selected through scheduled sampling. Information pertaining to demographic and correlates of RTI was collected by face to face and over telephone using semi-structured questionnaire. Nine-item Simplified Injury Severity Scale (SISS) was used to assess injury severity. Internal consistency of SISS scale was showed by Cronbach's alpha and association with the correlates was done by Mann-Whitney U-test. STATISTICAL ANALYSIS USED: With SPSS version 22.0, binary logistic regression, and Mann-Whitney U-test. RESULTS AND CONCLUSION: Fatal outcome in terms of death and permanent disability was 34.24% and they had higher marginally significant (P = 0.06), SISS score (45.17 ± 12.59). Participants with absence of protective devices, presence of comorbidities, drunkenness, with accidents over national highways, in-between 6 am and 6 pm, mechanized two-wheelers, and nonreceipt of first aid were found to have significantly high scores compared to their counterpart. SISS, as a proxy measure of severity assessment, could throw a light on it and awareness generation and legislative stringency might be need of the hour for the country.

Effect of Inactivating Mutations on Peptide Conformational Ensembles: The Plant Polypeptide Hormone Systemin.

As part of their basal immune mechanism against insect/herbivore attacks, plants have evolved systemic response mechanisms. Such a systemic wound response in tomato was found to involve an 18 amino acid polypeptide called systemin, the first polypeptide hormone to be discovered in plants. Systematic alanine scanning and deletion studies showed differential modulation in its activity, particularly a major loss of function due to alanine substitution at positions 13 and 17 and less extentive loss of function due to substitution at position 12. We have studied the conformational ensembles of wild-type systemin along with its 17 variants by carrying out a total of 5.76 µs of replica-exchange molecular dynamics simulation in an implicit solvent environment. In our simulations, wild-type systemin showed a lack of α-helical and ß-sheet structures, in conformity with earlier circular dichroism and NMR data. On the other hand, two regions containing diproline segments showed a tendency to adopt polyproline II structures. Examination of conformational ensembles of the 17 variants revealed a change in the population distributions, suggesting a less flexible structure for alanine substitutions at positions 12 and 13 but not for position 17. Combined with the experimental observations that positions 1-14 of systemin are important for the formation of the peptide-receptor complex, this leads to the hypothesis that loss of conformational flexibility may play a role in the loss of activity of systemin due to the P12A and P13A substitutions, while T17A deactivation probably occurs for a different reason, most likely the loss of the threonine phosphorylation site. We also indicate possible structural reasons why the substitution of the prolines at positions 12 and 13 leads to a loss of conformational freedom in the peptide.