QuadBase: genome-wide database of G4 DNA—occurrence and conservation in human, chimpanzee, mouse and rat promoters and 146 microbes

Emerging evidence indicates the importance of G-quadruplex motifs as drug targets. [Stuart A. Borman, Ascent of quadruplexes—nucleic acid structures become promising drug targets. Chem. Eng. News, 2007;85, 12–17], which stems from the fact that these motifs are present in a surprising number of promoters wherein their role in controlling gene expression has been demonstrated for a few. We present a compendium of quadruplex motifs, with particular focus on their occurrence and conservation in promoters—QuadBase. It is composed of two parts (EuQuad and ProQuad). EuQuad gives information on quadruplex motifs present within 10 kb of transcription starts sites in 99 980 human, chimpanzee, rat and mouse genes. ProQuad contains quadruplex information of 146 prokaryotes. Apart from gene-specific searches for quadruplex motifs, QuadBase has a number of other modules. ‘Orthologs Analysis’ queries for conserved motifs across species based on a selected reference organism; ‘Pattern Search’ can be used to fetch specific motifs of interest from a selected organism using user-defined criteria for quadruplex motifs, i.e. stem, loop size, etc. ‘Pattern Finder’ tool can search for motifs in any given sequence. QuadBase is freely available to users from non-profit organization at http://quadbase.igib.res.in/

Impact of raw material surface oxide removal on dual band infrared optical properties of As2Se3 chalcogenide glass

The manufacturing of low loss chalcogenide glasses (ChGs) for optoelectronic applications is ultimately defined by the concentration of impurities present in starting materials or imparted via processing. We describe a rapid method for purifying metallic starting materials in As2Se3 glass where oxide reduction is correlated to optical and physical properties. Specifically, As-O reduction enhances the glass' dual-band optical transparency proportional to the extent (13-fold reduction) of oxide reduction, and is accompanied by a change in density and hardness associated with changes in matrix bonding. A significant modification of the glass' index and LWIR Abbe number is reported highlighting the significant impact purification has on material dispersion control required in optical designs. (C) 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreemen

Promoter-proximal transcription factor binding is transcriptionally active when coupled with nucleosome repositioning in immediate vicinity

Previous studies have analyzed patterns of transcription, Transcription Factor (TF) binding or mapped nucleosome occupancy across the genome. These suggest that the three aspects are genetically connected but the cause and effect relationships are still unknown. For example, physiologic TF binding studies involve many TFs, consequently, it is difficult to assign nucleosome reorganization to the binding site occupancy of any particular TF. Therefore, several aspects remain unclear: does TF binding influence nucleosome (re)organizations locally or impact the chromatin landscape at a more global level; are all or only a fraction of TF binding a result of reorganization in nucleosome occupancy and do all TF binding and associated changes in nucleosome occupancy result in altered gene expression? With these in mind, following characterization of two states (before and after induction of a single TF of choice) we determined: (i) genomic binding sites of the TF, (ii) promoter nucleosome occupancy and (iii) transcriptome profiles. Results demonstrated that promoter-proximal TF binding influenced expression of the target gene when it was coupled to nucleosome repositioning at or close to its binding site in most cases. In contrast, only in few cases change in target gene expression was found when TF binding occurred without local nucleosome reorganization

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

EFFICACY OF MIXED MS2-L2 VLPS AGAINST SIX HPV TYPES AND THE DEVELOPMENT & EVALUATION OF VIRAL STRUCTURAL PROTEINS FOR ASSEMBLY INTO VLPS

Virus-like particles (VLPs) are empty viral shells derived from the expression of viral structural proteins such as capsid (coat) proteins in a suitable host cell. They are morphologically and structurally similar to viruses from which the coat proteins were derived, except for the fact that they lack the viral genome; thus, they are very safe. VLPs are highly immunogenic and have been used as vaccines against viruses from which the coat proteins were derived as well as vaccine platforms to develop vaccines against other infectious agents. However, VLPs derived from viruses that infect humans have some limitations; for example, pre-existing antibodies against some of these platforms already exist in the human population and can attenuate the immunogenicity of some of these platforms. As an alternative to using VLPs from human viruses, our lab used VLPs from a virus (MS2) that infects bacteria (bacteriophage) to develop a candidate vaccine against human papillomaviruses (HPVs). The candidate vaccine consisted of a mixture of two (mixed) MS2-L2 VLPs displaying a concatemer peptide from HPV16L2/HPV31L2 and a consensus peptide from HPVs. In this dissertation, we showed that immunization with mixed MS2-L2 VLPs protects mice against six HPV types; at the genital region, the VLPs protect against HPV pseudoviruses (PsVs) 5, 6, 11, 51, and 56. In the oral region, the VLPs protect against HPV PsV52. Overall, this part of the study shows that mixed MS2-L2 VLPs can protect against three HPV types associated with ~4.5% of cervical cancers, two HPV types associated with ~90% of genital warts and \u3e90% recurrent respiratory papillomatosis; additionally, the VLPs protect against one of two HPV types associated with ~90% of HPV-associated skin cancers in patients with epidermodysplasia verruciformis. More importantly, we observed that mixed MS2L2 VLPs elicit protective antibodies that last over 9 months; furthermore, a sprayfreeze dried formulation of the VLPs is thermostable, immunogenic, and protective at room temperature for over 5 months and at 37 °C for 2 months. Given the degree of success in using bacteriophage MS2 VLPs, as a platform to develop a candidate vaccine against HPV, we also explored in this dissertation whether VLPs from other viruses (especially bacteriophages) can be developed, which could one day serve as platforms for vaccines. We assessed whether co-expression, in a thermophilic bacterium E. coli, of three coat proteins (VP11, VP16, and VP17) from a thermophilic bacteriophage, P23-77, can allow the coat proteins to assemble into VLPs. For the first time, we successfully co-expressed all three coat proteins in E. coli and observed oval structures that look like VLPs but are smaller in size compared to P23-77 virus

Predicting the Spread of Malware Outbreaks Using Autoencoder Based Neutral Networks

Malware Outbreaks are pervasive in today's digital world. However, there is a lack of awareness on part of general public on how to safeguard against such attacks and a need for increased cooperation between various national and international research as well as governmental organizations to combat the threat. On the positive side, cyber security websites, blogs and newsletters post articles outlining the working and spread of a malware outbreak and steps to recover from the same as well. In this project, an effective approach to predicting the spread of malware outbreaks is presented. The scope of the project is 15 Malware Outbreaks and the approach involves collecting these cyber aware articles from the web, assigning them to the 15 Malware Outbreaks using Topic Modeling and Similarity Analysis and along with Spread information of the Malware Outbreaks, this is input to auto encoder neural network for learning latent space representations which are further used to predict the spread of malware outbreak as either high or low spread outbreak, achieving a prediction accuracy of 75.56. This work can be used to process large amount of cyber aware content for effective and accurate prediction in the era of much-needed cyber security

Current Clinical Trial Landscape of OX40 Agonists.

PURPOSE OF REVIEW: Despite the efficacy of immune checkpoint blockade (ICB) immunotherapy, most cancer patients still develop progressive disease necessitating additional treatment options. One approach is ligation of the OX40 (CD134) costimulatory receptor which promotes T cell activation, effector function, and the generation of long-lived memory cells. RECENT FINDINGS: Numerous preclinical studies have demonstrated that OX40 agonists alone or in combination with ICB (e.g., anti-PD-1, anti-PD-L1, and anti-CTLA-4) augment anti-tumor immunity. In this review, we discuss the impact of OX40 agonists on T cell function and the therapeutic potential of OX40 agonists alone or in conjunction with ICB for patients with advanced malignancies

Virus-like particle-based L2 vaccines against HPVs: Where are we today?

Human papillomaviruses (HPVs) are the most common sexually transmitted infections worldwide. Ninety percent of infected individuals clear the infection within two years; however, in the remaining 10% of infected individuals, the infection(s) persists and ultimately leads to cancers (anogenital cancers and head and neck cancers) and genital warts. Fortunately, three prophylactic vaccines have been approved to protect against HPV infections. The most recent HPV vaccine, Gardasil-9 (a nonavalent vaccine), protects against seven HPV types associated with ~90% of cervical cancer and against two HPV types associated with ~90% genital warts with little cross-protection against non-vaccine HPV types. The current vaccines are based on virus-like particles (VLPs) derived from the major capsid protein, L1. The L1 protein is not conserved among HPV types. The minor capsid protein, L2, on the other hand, is highly conserved among HPV types and has been an alternative target antigen, for over two decades, to develop a broadly protective HPV vaccine. The L2 protein, unlike the L1, cannot form VLPs and as such, it is less immunogenic. This review summarizes current studies aimed at developing HPV L2 vaccines by multivalently displaying L2 peptides on VLPs derived from bacteriophages and eukaryotic viruses. Recent data show that a monovalent HPV L1 VLP as well as bivalent MS2 VLPs displaying HPV L2 peptides (representing amino acids 17-36 and/or consensus amino acids 69-86) elicit robust broadly protective antibodies against diverse HPV types (6/11/16/18/26/31/33/34/35/39/43/44/45/51/52/53/56/58/59/66/68/73) associated with cancers and genital warts. Thus, VLP-based L2 vaccines look promising and may be favorable, in the near future, over current L1-based HPV vaccines and should be explored further

Clinical and metabolic characteristics in hidradenitis suppurativa – An Indian perspective

Background: Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent follicular disorder affecting apocrine gland bearing areas such as axillae, inframammary area and groin. Significant association of HS with metabolic derangements such as hypertension, obesity, hyperlipidemia and hyperinsulinemia has been found. There is dearth of literature on epidemiological and metabolic profile of HS in Indian subjects. Aim: The aim of this study is to assess abnormalities in the levels of fasting blood glucose, serum insulin, and lipid profile in patients with HS. Primary Objective: To assess the frequency of abnormal levels of fasting blood sugar, serum insulin and lipid profile in patients with HS. Secondary objectives: To assess the frequency of hypertension, raised basal metabolic index, polycystic ovarian syndrome, follicular disorder, erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) in patients with HS and to assess the severity of of clinical presentation HS using Hurley staging system. Methodology: This is a retrospective record based study. Records of clinically diagnosed patients of HS, aged > 18 years fulfilling the inclusion and exclusion criteria were analysed. Results: Total 30 patients were recruited with 1:1 male to female ratio. Five (16.67%) cases fulfilled NCEP ATP III criteria for the diagnosis of metabolic syndrome. Statistically significant association was observed between severity of HS, in younger age group (<20 years), moderate to severe BMI, fasting serum insulin, fasting total cholesterol and raised ESR. Limitations: This is retrospective, hospital record based study with small sample size. Conclusion: Holistic management of HS should be individualized according to need of patient and it should be combined approach including dermatologist, plastic surgeon, psychiatrist and dietician. We recommend an initial screening for derangements in metabolic profile in these patients for more effective management and preventing long term cardiovascular complications

Mixed bacteriophage ms2-l2 vlps elicit long-lasting protective antibodies against hpv pseudovirus 51

Three prophylactic vaccines are approved to protect against HPV infections. These vaccines are highly immunogenic. The most recent HPV vaccine, Gardasil-9, protects against HPV types associated with ~90% of cervical cancer (worldwide). Thus, ~10% of HPV-associated cancers are not protected by Gardasil-9. Although this is not a large percentage overall, the HPV types associated with 10% of cervical cancer not protected by the current vaccine are significantly important, especially in HIV/AIDS patients who are infected with multiple HPV types. To broaden the spectrum of protection against HPV infections, we developed mixed MS2-L2 VLPs (MS2-31L2/16L2 VLPs and MS2-consL2 (69-86) VLPs) in a previous study. Immunization with the VLPs neutralized/protected mice against infection with eleven high-risk HPV types associated with ~95% of cervical cancer and against one low-risk HPV type associated with ~36% of genital warts & up to 32% of recurrent respiratory papillomatosis. Here, we report that the mixed MS2-L2 VLPs can protect mice from three additional HPV types: HPV51, which is associated with ~0.8% of cervical cancer; HPV6, which is associated with up to 60% of genital warts; HPV5, which is associated with skin cancers in patients with epidermodysplasia verruciformis (EV). Overall, mixed MS2-L2 VLPs can protect against twelve HPV types associated with ~95.8% of cervical cancers and against two HPV types associated with ~90% of genital warts and \u3e90% recurrent respiratory papillomatosis. Additionally, the VLPs protect against one of two HPV types associated with ~90% of HPV-associated skin cancers in patients with EV. More importantly, we observed that mixed MS2-L2 VLPs elicit protective antibodies that last over 9 months. Furthermore, a spray-freeze-dried formulation of the VLPs is stable, immunogenic, and protective at room temperature and 37◦C