Quadruplex-single nucleotide polymorphisms (Quad-SNP) influence gene expression difference among individuals

Non-canonical guanine quadruplex structures are not only predominant but also conserved among bacterial and mammalian promoters. Moreover recent findings directly implicate quadruplex structures in transcription. These argue for an intrinsic role of the structural motif and thereby posit that single nucleotide polymorphisms (SNP) that compromise the quadruplex architecture could influence function. To test this, we analysed SNPs within quadruplex motifs (Quad-SNP) and gene expression in 270 individuals across four populations (HapMap) representing more than 14 500 genotypes. Findings reveal significant association between quadruplex-SNPs and expression of the corresponding gene in individuals (P < 0.0001). Furthermore, analysis of Quad-SNPs obtained from population-scale sequencing of 1000 human genomes showed relative selection bias against alteration of the structural motif. To directly test the quadruplex-SNP-transcription connection, we constructed a reporter system using the RPS3 promoter—remarkable difference in promoter activity in the ‘quadruplex-destabilized’ versus ‘quadruplex-intact’ promoter was noticed. As a further test, we incorporated a quadruplex motif or its disrupted counterpart within a synthetic promoter reporter construct. The quadruplex motif, and not the disrupted-motif, enhanced transcription in human cell lines of different origin. Together, these findings build direct support for quadruplex-mediated transcription and suggest quadruplex-SNPs may play significant role in mechanistically understanding variations in gene expression among individuals

The genomic and transcriptional landscape of primary central nervous system lymphoma

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations

The genomic and transcriptional landscape of primary central nervous system lymphoma

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Re-colonizing Mangrove species in tsunami devastated habitats at Nicobar Islands, India

Mangrove habitats are crucial for maintaining the biodiversity of coastal ecosystem. Climatic change, sea level rise and anthropogenic pressures are the major threats to mangrove forests. The Nicobar Islands comprised one of the pristine mangrove stands in India. The mega earthquake of >9 M and subsequent tsunami during 2004 caused destruction of over 70% of mangrove vegetation in Nicobar Islands. The present study was carried out in the Central Nicobar Group of Islands (Camorta, Nancowry, Katchall and Trinkat), where tsunami has entirely wiped out the mangrove vegetation. Re-colonization started on its own course. We enumerated nine species of mangrove plants and 30 species of mangrove associates from the surveyed locations. Lumnitzera racemosa has been recorded for the first time from the study area. Rhizophora mucronata and Bruguiera gymnorrhiza were the common pioneer mangrove species. Long-term monitoring of re-colonization process will help us in understanding succession of mangrove forests

Chemomodulatory effects of Ichnocarpus frutescens R. Br against 4-vinylcyclohexane induced ovarian cancer in swiss albino mice

Objective: To evaluate the protective effect of Ichnocarpus frutescens (I. frutescens) R. Br against 4-vinylcyclohexane induced ovarian cancer in Swiss albino mice. Methods: The ovarian cancer was induced by 4-vinylcyclohexane which was given to 28-day-old mice in corn oil, intra peritoneally, at 2.7 mmol/kg body weight/day for 30 d. After that serum and tissue were isolated. Enzymatic antioxidants, non-enzymatic antioxidants, lipid peroxidation assessed in liver and ovary homogenate. Metabolites, marker enzymes were analyzed in serum. Tissue was examined histopathology examination. Results: The levels of urea, creatinine, marker enzymes and lipid peroxidation were significantly increased in ovarian cancer induced mice when compared to control group whereas, levels of uric acid, enzymatic and non-enzymatic antioxidants were decreased in cancer induced mice when compared with control mice. From these parameters were brought back to near normal in ethanolic extract of I. frutescens treated animals. The above results were further confirmed by histopathological examination which shows marked edema of lamina propria occurred in cancer induced animals whereas no alterations in ethanolic extract of I. frutescens and cisplatin treated groups. Conclusions: This present study was evaluated that the ethanolic extracts of I. frutescens have effective anticancer activity against 4-vinylcyclohexane induced ovarian cancer

Cellular uptake and binding of guanidine-modified phthalocyanines to KRAS/HRAS G-quadruplexes

Guanidino-modified phthalocyanines are evaluated in vitro (polymerase-stop assays and FRET) and in cultured cells as G4-DNA ligands and modulators of gene transcription

One-Pot Synthesis of Silver Nanoparticles Derived from Aqueous Leaf Extract of <i>Ageratum conyzoides</i> and Their Biological Efficacy

The main objective of the present research work is to assess the biological properties of the aqueous plant extract (ACAE) synthesised silver nanoparticles from the herbal plant Ageratum conyzoides, and their biological applications. The silver nanoparticle syntheses from Ageratum conyzoides (Ac-AgNPs) were optimised with different parameters, such as pH (2, 4, 6, 8 and 10) and varied silver nitrate concentration (1 mM and 5 mM). Based on the UV–vis spectroscopy analysis of the synthesised silver nanoparticles, the concentration of 5 mM with the pH at 8 was recorded as the peak reduction at 400 nm; and these conditions were optimized were used for further studies. The results of the FE-SEM analysis recorded the size ranges (~30–90 nm), and irregular spherical and triangular shapes of the AC-AgNPs were captured. The characterization reports of the HR-TEM investigation of AC-AgNPs were also in line with the FE-SEM studies. The antibacterial efficacies of AC-AgNPs have revealed the maximum zone of inhibition against S. typhi to be within 20 mm. The in vitro antiplasmodial activity of AC-AgNPs is shown to have an effective antiplasmodial property (IC50:17.65 μg/mL), whereas AgNO3 has shown a minimum level of IC50: value 68.03 μg/mL, and the Ac-AE showed >100 μg/mL at 24 h of parasitaemia suppression. The α-amylase inhibitory properties of AC-AgNPs have revealed a maximum inhibition similar to the control Acarbose (IC50: 10.87 μg/mL). The antioxidant activity of the AC-AgNPs have revealed a better property (87.86% ± 0.56, 85.95% ± 1.02 and 90.11 ± 0.29%) when compared with the Ac-AE and standard in all the three different tests, such as DPPH, FRAP and H2O2 scavenging assay, respectively. The current research work might be a baseline for the future drug expansion process in the area of nano-drug design, and its applications also has a lot of economic viability and is a safer method in synthesising or producing silver nanoparticles