Evolutionary impact of chimeric RNAs on generating phenotypic plasticity in human cells.

Chimeric RNAs are generated by the fusion of the exons or introns of two genes. The generation of chimeric RNAs is important for the functional expansion of cells. Here, we describe the functional implications of chimeric RNAs for generating phenotypic plasticity from an evolutionary perspective.

A computational approach for the identification of distant homologs of bacterial riboswitches based on inverse RNA folding.

Riboswitches are conserved structural ribonucleic acid (RNA) sensors that are mainly found to regulate a large number of genes/operons in bacteria. Presently, >50 bacterial riboswitch classes have been discovered, but only the thiamine pyrophosphate riboswitch class is detected in a few eukaryotes like fungi, plants and algae. One of the most important challenges in riboswitch research is to discover existing riboswitch classes in eukaryotes and to understand the evolution of bacterial riboswitches. However, traditional search methods for riboswitch detection have failed to detect eukaryotic riboswitches besides just one class and any distant structural homologs of riboswitches. We developed a novel approach based on inverse RNA folding that attempts to find sequences that match the shape of the target structure with minimal sequence conservation based on key nucleotides that interact directly with the ligand. Then, to support our matched candidates, we expanded the results into a covariance model representing similar sequences preserving the structure. Our method transforms a structure-based search into a sequence-based search that considers the conservation of secondary structure shape and ligand-binding residues. This method enables us to identify a potential structural candidate in fungi that could be the distant homolog of bacterial purine riboswitches. Further, phylogenomic analysis and evolutionary distribution of this structural candidate indicate that the most likely point of origin of this structural candidate in these organisms is associated with the loss of traditional purine riboswitches. The computational approach could be applicable to other domains and problems in RNA research.

The nepenthesin insert in the Plasmodium falciparum aspartic protease plasmepsin V is necessary for enzyme function.

Plasmepsin V (PM V) is a pepsin-like aspartic protease essential for growth of the malarial parasite Plasmodium falciparum. Previous work has shown PM V to be an endoplasmic reticulum-resident protease that processes parasite proteins destined for export into the host cell. Depletion or inhibition of the enzyme is lethal during asexual replication within red blood cells as well as during the formation of sexual stage gametocytes. The structure of the Plasmodium vivax PM V has been characterized by X-ray crystallography, revealing a canonical pepsin fold punctuated by structural features uncommon to secretory aspartic proteases; however, the function of this unique structure is unclear. Here, we used parasite genetics to probe these structural features by attempting to rescue lethal PM V depletion with various mutant enzymes. We found an unusual nepenthesin 1-type insert in the PM V gene to be essential for parasite growth and PM V activity. Mutagenesis of the nepenthesin insert suggests that both its amino acid sequence and one of the two disulfide bonds that undergird its structure are required for the insert's role in PM V function. Furthermore, molecular dynamics simulations paired with Markov state modeling suggest that mutations to the nepenthesin insert may allosterically affect PM V catalysis through multiple mechanisms. Taken together, these data provide further insights into the structure of the P. falciparum PM V protease.

COVID19 Drug Repository: text-mining the literature in search of putative COVID19 therapeutics.

The recent outbreak of COVID-19 has generated an enormous amount of Big Data. To date, the COVID-19 Open Research Dataset (CORD-19), lists ∼130,000 articles from the WHO COVID-19 database, PubMed Central, medRxiv, and bioRxiv, as collected by Semantic Scholar. According to LitCovid (11 August 2020), ∼40,300 COVID19-related articles are currently listed in PubMed. It has been shown in clinical settings that the analysis of past research results and the mining of available data can provide novel opportunities for the successful application of currently approved therapeutics and their combinations for the treatment of conditions caused by a novel SARS-CoV-2 infection. As such, effective responses to the pandemic require the development of efficient applications, methods and algorithms for data navigation, text-mining, clustering, classification, analysis, and reasoning. Thus, our COVID19 Drug Repository represents a modular platform for drug data navigation and analysis, with an emphasis on COVID-19-related information currently being reported. The COVID19 Drug Repository enables users to focus on different levels of complexity, starting from general information about (FDA-) approved drugs, PubMed references, clinical trials, recipes as well as the descriptions of molecular mechanisms of drugs' action. Our COVID19 drug repository provide a most updated world-wide collection of drugs that has been repurposed for COVID19 treatments around the world.

Sterol 14-α-demethylase is vital for mitochondrial functions and stress tolerance in Leishmania major.

Sterol 14-α-demethylase (C14DM) is a key enzyme in the biosynthesis of sterols and the primary target of azoles. In Leishmania major, genetic or chemical inactivation of C14DM leads to accumulation of 14-methylated sterol intermediates and profound plasma membrane abnormalities including increased fluidity and failure to maintain ordered membrane microdomains. These defects likely contribute to the hypersensitivity to heat and severely reduced virulence displayed by the C14DM-null mutants (c14dm‾). In addition to plasma membrane, sterols are present in intracellular organelles. In this study, we investigated the impact of C14DM ablation on mitochondria. Our results demonstrate that c14dm‾ mutants have significantly higher mitochondrial membrane potential than wild type parasites. Such high potential leads to the buildup of reactive oxygen species in the mitochondria, especially under nutrient-limiting conditions. Consistent with these mitochondrial alterations, c14dm‾ mutants show impairment in respiration and are heavily dependent on glucose uptake and glycolysis to generate energy. Consequently, these mutants are extremely sensitive to glucose deprivation and such vulnerability can be rescued through the supplementation of glucose or glycerol. In addition, the accumulation of oxidants may also contribute to the heat sensitivity exhibited by c14dm‾. Finally, genetic or chemical ablation of C14DM causes increased susceptibility to pentamidine, an antimicrobial agent with activity against trypanosomatids. In summary, our investigation reveals that alteration of sterol synthesis can negatively affect multiple cellular processes in Leishmania parasites and make them vulnerable to clinically relevant stress conditions.

Identifying long-term effects of SARS-CoV-2 and their association with social determinants of health in a cohort of over one million COVID-19 survivors.

BACKGROUND: Despite an abundance of information on the risk factors of SARS-CoV-2, there have been few US-wide studies of long-term effects. In this paper we analyzed a large medical claims database of US based individuals to identify common long-term effects as well as their associations with various social and medical risk factors. METHODS: The medical claims database was obtained from a prominent US based claims data processing company, namely Change Healthcare. In addition to the claims data, the dataset also consisted of various social determinants of health such as race, income, education level and veteran status of the individuals. A self-controlled cohort design (SCCD) observational study was performed to identify ICD-10 codes whose proportion was significantly increased in the outcome period compared to the control period to identify significant long-term effects. A logistic regression-based association analysis was then performed between identified long-term effects and social determinants of health. RESULTS: Among the over 1.37 million COVID patients in our datasets we found 36 out of 1724 3-digit ICD-10 codes to be statistically significantly increased in the post-COVID period (p-value < 0.05). We also found one combination of ICD-10 codes, corresponding to 'other anemias' and 'hypertension', that was statistically significantly increased in the post-COVID period (p-value < 0.05). Our logistic regression-based association analysis with social determinants of health variables, after adjusting for comorbidities and prior conditions, showed that age and gender were significantly associated with the multiple long-term effects. Race was only associated with 'other sepsis', income was only associated with 'Alopecia areata' (autoimmune disease causing hair loss), while education level was only associated with 'Maternal infectious and parasitic diseases' (p-value < 0.05). CONCLUSION: We identified several long-term effects of SARS-CoV-2 through a self-controlled study on a cohort of over one million patients. Furthermore, we found that while age and gender are commonly associated with the long-term effects, other social determinants of health such as race, income and education levels have rare or no significant associations.

Identifying Hub Genes Associated with Neoadjuvant Chemotherapy Resistance in Breast Cancer and Potential Drug Repurposing for the Development of Precision Medicine.

Breast cancer is the second leading cause of morbidity and mortality in women worldwide. Despite advancements in the clinical application of neoadjuvant chemotherapy (NAC), drug resistance remains a major concern hindering treatment efficacy. Thus, identifying the key genes involved in driving NAC resistance and targeting them with known potential FDA-approved drugs could be applied to advance the precision medicine strategy. With this aim, we performed an integrative bioinformatics study to identify the key genes associated with NAC resistance in breast cancer and then performed the drug repurposing to identify the potential drugs which could use in combination with NAC to overcome drug resistance. In this study, we used publicly available RNA-seq datasets from the samples of breast cancer patients sensitive and resistant to chemotherapy and identified a total of 1446 differentially expressed genes in NAC-resistant breast cancer patients. Next, we performed gene co-expression network analysis to identify significantly co-expressed gene modules, followed by MCC (Multiple Correlation Clustering) clustering algorithms and identified 33 key hub genes associated with NAC resistance. mRNA-miRNA network analysis highlighted the potential impact of these hub genes in altering the regulatory network in NAC-resistance breast cancer cells. Further, several hub genes were found to be significantly involved in the poor overall survival of breast cancer patients. Finally, we identified FDA-approved drugs which could be useful for potential drug repurposing against those hub genes. Altogether, our findings provide new insight into the molecular mechanisms of NAC resistance and pave the way for drug repurposing techniques and personalized treatment to overcome NAC resistance in breast cancer.

Capturing COVID-19-Like Symptoms at Scale Using Banner Ads on an Online News Platform: Pilot Survey Study.

BACKGROUND: Identifying new COVID-19 cases is challenging. Not every suspected case undergoes testing, because testing kits and other equipment are limited in many parts of the world. Yet populations increasingly use the internet to manage both home and work life during the pandemic, giving researchers mediated connections to millions of people sheltering in place. OBJECTIVE: The goal of this study was to assess the feasibility of using an online news platform to recruit volunteers willing to report COVID-19-like symptoms and behaviors. METHODS: An online epidemiologic survey captured COVID-19-related symptoms and behaviors from individuals recruited through banner ads offered through Microsoft News. Respondents indicated whether they were experiencing symptoms, whether they received COVID-19 testing, and whether they traveled outside of their local area. RESULTS: A total of 87,322 respondents completed the survey across a 3-week span at the end of April 2020, with 54.3% of the responses from the United States and 32.0% from Japan. Of the total respondents, 19,631 (22.3%) reported at least one symptom associated with COVID-19. Nearly two-fifths of these respondents (39.1%) reported more than one COVID-19-like symptom. Individuals who reported being tested for COVID-19 were significantly more likely to report symptoms (47.7% vs 21.5%; P<.001). Symptom reporting rates positively correlated with per capita COVID-19 testing rates (R2=0.26; P<.001). Respondents were geographically diverse, with all states and most ZIP Codes represented. More than half of the respondents from both countries were older than 50 years of age. CONCLUSIONS: News platforms can be used to quickly recruit study participants, enabling collection of infectious disease symptoms at scale and with populations that are older than those found through social media platforms. Such platforms could enable epidemiologists and researchers to quickly assess trends in emerging infections potentially before at-risk populations present to clinics and hospitals for testing and/or treatment.

Clinicopathological characteristics, prognostic factors and treatment outcomes of seminomatous germ cell tumours from a tertiary cancer centre in eastern India.

Background: . Seminomatous germ cell tumour (SGCT) is a rare but curable malignancy of young adults. The literature on management and outcome of SGCT is scarce from India. We report the demography and treatment outcome of SGCT at our centre. Methods: . We did a retrospective analysis of patients with SGCT treated from March 2011 to December 2018. Patients were staged appropriately with imaging, and pre- and postoperative tumour markers. High inguinal orchiectomy was performed in all with a testicular primary and received subsequent stage-adjusted adjuvant treatment. Patients were monitored for metabolic syndrome during follow-up after completion of treatment. Results: . We treated 85 patients with a median age of 37 (range 20-68) years. The primary site of the tumour was the testis in 80 (94%) and mediastinum in 5 (6%) patients. Cryptorchidism was present in 20 (25%) patients and testicular violation was present in 11 (14%) patients. Stage of the disease was I in 61, II in 13 and III in 6 patients. Adjuvant treatment in stage I disease was single-agent carbo-platin (area under the curve ×7) in 38 (62%), surveillance in 20 (33%) and radiotherapy in 3 (5%) patients. Five patients in the surveillance group relapsed. The 7-year mean (SD) relapse-free survival and overall survival were 83.1% (8%) and 98.7% (1.3%), respectively. Thirty-one patients (n = 52, 60%) had features of metabolic syndrome. Conclusions: . SGCTs have a high cure rate. Long-term follow-up is essential for monitoring toxic effects. Early diagnosis, avoidance of testicular violation and multidisciplinary management are the key features for better long-term outcome in SGCT.

A New Perspective on Cancer Therapy: Changing the Treaded Path?

During the last decade, we have persistently addressed the question, "how can the innate immune system be used as a therapeutic tool to eliminate cancer?" A cancerous tumor harbors innate immune cells such as macrophages, which are held in the tumor-promoting M2 state by tumor-cell-released cytokines. We have discovered that these tumor-associated macrophages (TAM) are repolarized into the nitric oxide (NO)-generating tumoricidal M1 state by the dietary agent curcumin (CC), which also causes recruitment of activated natural killer (NK) cells and cytotoxic T (Tc) cells into the tumor, thereby eliminating cancer cells as well as cancer stem cells. Indications are that this process may be NO-dependent. Intriguingly, the maximum blood concentration of CC in mice never exceeds nanomolar levels. Thus, our results submit that even low, transient levels of curcumin in vivo are enough to cause repolarization of the TAM and recruitment NK cells as well as Tc cells to eliminate the tumor. We have observed this phenomenon in two cancer models, glioblastoma and cervical cancer. Therefore, this approach may yield a general strategy to fight cancer. Our mechanistic studies have so far implicated induction of STAT-1 in this M2→M1 switch, but further studies are needed to understand the involvement of other factors such as the lipid metabolites resolvins in the CC-evoked anticancer pathways.

Sterol methyltransferase is required for optimal mitochondrial function and virulence in Leishmania major.

Limited knowledge on the exact functions of ergostane-based sterols has hampered the application of sterol synthesis inhibitors against trypanosomatid parasites. Sterol methyltransferase (SMT) is directly involved in the synthesis of parasite-specific C24-methylated sterols, including ergosterol and 5-dehydroepisterol. While pharmacological studies hint at its potential as a drug target against trypanosomatids, direct evidence for the cellular function and essentiality of SMT is lacking. Here, we characterized the SMT knockout mutants and their complemented strains in Leishmania major, the causative agent for cutaneous leishmaniasis. Deletion of SMT alleles led to a complete loss of C24-methylated sterols, which were replaced by cholestane-based sterols. SMT-null mutants were fully viable and replicative in culture but showed increased sensitivity to sphingolipid synthesis inhibition. They were not particularly vulnerable to heat, acidic pH, nitrosative or oxidative stress, yet exhibited high mitochondrial membrane potential and increased superoxide generation indicating altered physiology of the mitochondria. Despite possessing high levels of GPI-anchored glycoconjugates, SMT-null mutants showed significantly attenuated virulence in mice. In total, our study reveals that the biosynthesis of ergostane-based sterols is crucial for the proper function of mitochondria and the proliferation of Leishmania parasites in mammals.

RiboD: a comprehensive database for prokaryotic riboswitches.

SUMMARY: Riboswitches are cis-regulatory non-coding genomic segments that control the expression of downstream genes by undergoing conformational change upon ligand binding. We present a comprehensive database of prokaryotic riboswitches that allows the user to search for riboswitches using multiple criteria, extract information about riboswitch location and gene/operon it regulates. RiboD provides a very useful resource that can be utilized for the better understanding of riboswitch-based gene regulation in bacteria and archaea. AVAILABILITY AND IMPLEMENTATION: RiboD can be freely accessed on the web at http://ribod.iiserkol.ac.in/.

Identifying and ranking potential driver genes of Alzheimer's disease using multiview evidence aggregation.

MOTIVATION: Late onset Alzheimer's disease is currently a disease with no known effective treatment options. To better understand disease, new multi-omic data-sets have recently been generated with the goal of identifying molecular causes of disease. However, most analytic studies using these datasets focus on uni-modal analysis of the data. Here, we propose a data driven approach to integrate multiple data types and analytic outcomes to aggregate evidences to support the hypothesis that a gene is a genetic driver of the disease. The main algorithmic contributions of our article are: (i) a general machine learning framework to learn the key characteristics of a few known driver genes from multiple feature sets and identifying other potential driver genes which have similar feature representations, and (ii) A flexible ranking scheme with the ability to integrate external validation in the form of Genome Wide Association Study summary statistics. While we currently focus on demonstrating the effectiveness of the approach using different analytic outcomes from RNA-Seq studies, this method is easily generalizable to other data modalities and analysis types. RESULTS: We demonstrate the utility of our machine learning algorithm on two benchmark multiview datasets by significantly outperforming the baseline approaches in predicting missing labels. We then use the algorithm to predict and rank potential drivers of Alzheimer's. We show that our ranked genes show a significant enrichment for single nucleotide polymorphisms associated with Alzheimer's and are enriched in pathways that have been previously associated with the disease. AVAILABILITY AND IMPLEMENTATION: Source code and link to all feature sets is available at https://github.com/Sage-Bionetworks/EvidenceAggregatedDriverRanking.

Dietary infection of Enterobacter ludwigii causes fat accumulation and resulted in the diabetes-like condition in Drosophila melanogaster.

Bacteria as a foreign pathogen can alter the physiology and metabolism of the host. Many of the teeth infecting bacteria known to be associated with obesity and diabetes in various organisms. The current study aims to check the effect of teeth infecting bacteria Enterobacter ludwigii on model organism Drosophila melanogaster. To check the effect, various concentrations of E. ludwigii on fly physiology the bacteria were added to the fly food. Flies were allowed to grow and colonise in infected food. The offsprings were checked for the accumulation of lipid and fat. With the increase of bacteria within the gut the amount of lipid and fat increases. Alongwith the fat various biochemical parameters like glucose, trehalose, protein and triglyceride level found to be altered. Within the fly gut various metals, which have a role in the metabolism is altered. However, during colonisation within the gut, the morphology of the bacteria remains unaltered. In the adult fly, all the biochemical parameters like glucose, trehalose, protein and triglyceride level increased. The expression level of Dilp is upregulated. Altogether, the current study reports an infection of E. ludwigii causes the accumulation of fat and alters glucose metabolism in Drosophila melanogaster.

A cross-sectional study exploring disease characteristics and phylogenetic nature of human cytomegalovirus among infected neonates with congenital nephrotic syndrome.

BACKGROUND: Congenital nephrotic syndrome (CNS) is a rare but serious condition which affects neonates and is caused by monogenic defects of glomerular structural proteins or congenital viral infections. Several reports have established a causal relationship between human cytomegalovirus (HCMV) intrauterine infection and CNS, but thorough study assessing parameters has not yet been done. METHODS: This study aimed to ascertain significant demographic, biochemical, serological, inflammatory and etiological parameters with 12 months follow-up to clinically identify and monitor neonates with HCMV-associated CNS and sought to decipher the phylogenetic nature of infecting strains. Differences between four patient groups (neonates < 4 weeks old) with or without CNS and HCMV infection were compared by unpaired t testing and one-way analysis of variance (ANOVA). Linear regression was performed to assess statistical significance among individual groups. Maximum-likelihood-based phylogenetic analysis was performed with HCMV gH gene sequences to compare clinically isolated and referenced NCBI strains. This was further supported by analysis of effective number of codons (ENc), codon adaptation index (CAI) and mRNA structural variation. RESULTS: Patients with HCMV-associated CNS were found to have significant variations in many studied parameters compared with controls. The majority of clinical strains formed a separate phylogenetic cluster defining them as somewhat distinct from standard reference strains, which was supported by the other analyses. CONCLUSION: This study defined parameters for monitoring cases of HCMV-associated CNS, which suggest the possible existence of a selection force acting and rendering these HCMV strains able to infect selective host tissues and cause specific disease types.

Scalable preprocessing for sparse scRNA-seq data exploiting prior knowledge.

Motivation: Single cell RNA-seq (scRNA-seq) data contains a wealth of information which has to be inferred computationally from the observed sequencing reads. As the ability to sequence more cells improves rapidly, existing computational tools suffer from three problems. (i) The decreased reads-per-cell implies a highly sparse sample of the true cellular transcriptome. (ii) Many tools simply cannot handle the size of the resulting datasets. (iii) Prior biological knowledge such as bulk RNA-seq information of certain cell types or qualitative marker information is not taken into account. Here we present UNCURL, a preprocessing framework based on non-negative matrix factorization for scRNA-seq data, that is able to handle varying sampling distributions, scales to very large cell numbers and can incorporate prior knowledge. Results: We find that preprocessing using UNCURL consistently improves performance of commonly used scRNA-seq tools for clustering, visualization and lineage estimation, both in the absence and presence of prior knowledge. Finally we demonstrate that UNCURL is extremely scalable and parallelizable, and runs faster than other methods on a scRNA-seq dataset containing 1.3 million cells. Availability and implementation: Source code is available at https://github.com/yjzhang/uncurl_python. Supplementary information: Supplementary data are available at Bioinformatics online.

TriCurin, a synergistic formulation of curcumin, resveratrol, and epicatechin gallate, repolarizes tumor-associated macrophages and triggers an immune response to cause suppression of HPV+ tumors.

Our earlier studies reported a unique potentiated combination (TriCurin) of curcumin (C) with two other polyphenols. The TriCurin-associated C displays an IC50 in the low micromolar range for cultured HPV+ TC-1 cells. In contrast, because of rapid degradation in vivo, the TriCurin-associated C reaches only low nano-molar concentrations in the plasma, which are sub-lethal to tumor cells. Yet, injected TriCurin causes a dramatic suppression of tumors in TC-1 cell-implanted mice (TC-1 mice) and xenografts of Head and Neck Squamous Cell Carcinoma (HNSCC) cells in nude/nude mice. Here, we use the TC-1 mice to test our hypothesis that a major part of the anti-tumor activity of TriCurin is evoked by innate and adaptive immune responses. TriCurin injection repolarized arginase1high (ARG1high), IL10high, inducible nitric oxide synthaselow (iNOSlow), IL12low M2-type tumor-associated macrophages (TAM) into ARG1low, IL10low, iNOShigh, and IL12high M1-type TAM in HPV+ tumors. The M1 TAM displayed sharply suppressed STAT3 and induced STAT1 and NF-kB(p65). STAT1 and NF-kB(p65) function synergistically to induce iNOS and IL12 transcription. Neutralizing IL12 signaling with an IL12 antibody abrogated TriCurin-induced intra-tumor entry of activated natural killer (NK) cells and Cytotoxic T lymphocytes (CTL), thereby confirming that IL12 triggers recruitment of NK cells and CTL. These activated NK cells and CTL join the M1 TAM to elicit apoptosis of the E6+ tumor cells. Corroboratively, neutralizing IL12 signaling partially reversed this TriCurin-mediated apoptosis. Thus, injected TriCurin elicits an M2→M1 switch in TAM, accompanied by IL12-dependent intra-tumor recruitment of NK cells and CTL and elimination of cancer cells.

Liposomal TriCurin, A Synergistic Combination of Curcumin, Epicatechin Gallate and Resveratrol, Repolarizes Tumor-Associated Microglia/Macrophages, and Eliminates Glioblastoma (GBM) and GBM Stem Cells.

Glioblastoma (GBM) is a deadly brain tumor with a current mean survival of 12-15 months. Despite being a potent anti-cancer agent, the turmeric ingredient curcumin (C) has limited anti-tumor efficacy in vivo due to its low bioavailability. We have reported earlier a strategy involving the use two other polyphenols, epicatechin gallate (E) from green tea and resveratrol (R) from red grapes at a unique, synergistic molar ratio with C (C:E:R: 4:1:12.5, termed TriCurin) to achieve superior potency against HPV+ tumors than C alone at C:E:R (µM): 32:8:100 (termed 32 µM+ TriCurin). We have now prepared liposomal TriCurin (TrLp) and demonstrated that TrLp boosts activated p53 in cultured GL261 mouse GBM cells to trigger apoptosis of GBM and GBM stem cells in vitro. TrLp administration into mice yielded a stable plasma concentration of 210 nM C for 60 min, which, though sub-lethal for cultured GL261 cells, was able to cause repolarization of M2-like tumor (GBM)-associated microglia/macrophages to the tumoricidal M1-like phenotype and intra-GBM recruitment of activated natural killer cells. The intratumor presence of such tumoricidal immune cells was associated with concomitant suppression of tumor-load, and apoptosis of GBM and GBM stem cells. Thus, TrLp is a potential onco-immunotherapeutic agent against GBM tumors.

Riboswitch Scanner: an efficient pHMM-based web-server to detect riboswitches in genomic sequences.

UNLABELLED: Riboswitches are non-coding RNA located in the 5' untranslated regions where they bind a target metabolite used to specify the riboswitch class and control the expression of associated genes. Accurate identification of riboswitches is the first step towards understanding their regulatory and functional roles in the cell. In this article, we describe a new web application named Riboswitch Scanner which provides an automated pipeline for pHMM-based detection of riboswitches in partial as well as complete genomic sequences rapidly, with high sensitivity and specificity. AVAILABILITY AND IMPLEMENTATION: Riboswitch Scanner can be freely accessed on the web at http://service.iiserkol.ac.in/∼riboscan/ CONTACT: mukherjee.sumit89@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Curcumin changes the polarity of tumor-associated microglia and eliminates glioblastoma.

Glioblastoma (GBM) is one of the most pernicious forms of cancer and currently chances of survival from this malady are extremely low. We have used the noninvasive strategy of intranasal (IN) delivery of a glioblastoma-directed adduct of curcumin (CC), CC-CD68Ab, into the brain of mouse GBM GL261-implanted mice to study the effect of CC on tumor remission and on the phenotype of the tumor-associated microglial cells (TAMs). The treatment caused tumor remission in 50% of GL261-implanted GBM mice. A similar rescue rate was also achieved through intraperitoneal infusion of a lipid-encapsulated formulation of CC, Curcumin Phytosome, into the GL261-implanted GBM mice. Most strikingly, both forms of CC elicited a dramatic change in the tumor-associated Iba1+ TAMs, suppressing the tumor-promoting Arginase1high , iNOSlow M2-type TAM population while inducing the Arginase1low , iNOShigh M1-type tumoricidal microglia. Concomitantly, we observed a marked induction and activation of microglial NF-kB and STAT1, which are known to function in coordination to cause induction of iNOS. Therefore, our novel findings indicate that appropriately delivered CC can directly kill GBM cells and also repolarize the TAMs to the tumoricidal M1 state.