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Background: Hypertension is a cardiovascular disorder that is an incurable clinical condition. It requires lifelong therapy for its management along with long terms application of synthetic drugs associated with severe toxicity in multiple organs. However, the therapeutic application of herbal medicines to treat hypertension has gained considerable attention. The limitations and hurdles associated with conventional plant extract medications are their safety, efficacy, dose, and unknown biological activity. Objective: In the modern era, the active phytoconstituent-based formulation has come into trend. Various extraction techniques have been reported to extract and isolate active phytoconstituents. Pharmacognostic, physiochemical, phytochemical, and quantitative analytical methods were developed for their qualitative and quantitative analysis. The passage of time and changes in lifestyle also modulate the variable cause of hypertension. Single-drug-based approach therapy cannot efficiently control the cause of hypertension. Designing a potent herbal formulation with different active constituents and modes of action against hypertension is necessary to effectively manage hypertension. Method: This review comprises a selection of three different plants, Boerhavia diffusa, Rauwolfia Serpentina, and Elaeocarpus ganitrus exhibiting antihypertension activity. Result: The objective behind selecting individual plants is their active constituents which have different mechanisms of action for the treatment of hypertension. This review comprises the various extraction methods of the active phytoconstituents and pharmacognostic, physiochemical, phytochemical, and quantitative analysis parameters, respectively. It also lists active phytoconstituents present in plants and the different pharmacological modes of action. Selected plant extracts have different antihypertensive mechanisms. Extract of Boerhavia diffusa consisting of Liriodendron & Syringaresnol mono β-D-Glucosidase exhibit Ca2+ channel antagonistic activity; where Reserpine is a phytoconstituent of Rauwolfia serpentina, which depletes catecholamine, Ajmalin shows an antiarrhythmic effect by blocking the sodium channel and the aqueous extract of E. ganitrus seeds reduces mean arterial blood pressure by inhibiting the ACE enzyme. Conclusion: It has been revealed that poly-herbal formulation of respective phytoconstituent can be used as potent antihypertensive medicine to treat hypertension effectively.

The primary objective of the proposed research work is to extract and enrich pure andrographolide (AGL) by varying the polarity index and Hildebrand solubility parameter (δ) of a moderately polar solvent. Both parameters affect the solubility of AGL in different solvents and extraction methods. AGL was extracted from the whole plant Andrographis paniculata. Continuous or Direct, Maceration and Soxhlet extraction method used for extraction. Based on the appearance of the crystal in the direct Soxhlet ethyl acetate method, their yield was further optimized by using a randomized response surface (RSM) and quadratic model-based Box‒Behnken design (BBD). HPTLC was used to determine the AGL extraction efficiency, purity, and quantification. Based on the obtained result, the pure andrographolide crystal (yield 0.185 g/g) was obtained by direct Soxhlet extraction. Ethyl acetate is used as a solvent. The Rf exhibited in the TLC chromatogram was 0.28. The FT-IR spectra exhibited characteristic peaks similar to the standard AGL, and 1H-NMR and 13C NMR elucidated the crystal structure. The DEPT − 90/135 spectra showed that the extracted crystal was pure AGL. One of the novel approaches is isolating pure AGL crystals in a moderately polar solvent (ethyl acetate) by elevating the Hildebrand solubility parameter despite using polar solvents. AGL crystals were obtained from direct Soxhlet extraction by ethyl acetate. It is a single-step and more economical method. It can be easily transformed into a pilot or industrial setup to extract the pure AGL.

The primary objective of the proposed research work is to extract and enrich the pure Andrographolide (AGL) by varying the polarity index and Hildebrand solubility parameter (δ) of a moderately polar solvent. Both parameters affect the solubility of AGL in different solvents and extraction methods. AGL was extracted from the whole plant of Andrographis paniculata. Continuous or Direct, Maceration and Soxhlet extraction method used for extraction. Based on the appearance of the crystal in the Direct Soxhlet Ethyl acetate method, their yield was further optimized by using a Randomized response surface (RSM), Quadratic model-based Box-Behnken design (BBD). The HPTLC performed the AGL extraction efficiency, purity, and quantification. Based on the obtained result, the pure Andrographolide crystal (yield 0.185 g/g) was obtained by Direct Soxhlet extraction. Ethyl acetate is used as a solvent. Rf exhibited in the TLC chromatogram was 0.28. FT-IR spectra exhibited characteristics peak similar to the standard AGL, and 1H-NMR, 13C NMR elucidated crystal structure. DEPT − 90/135 spectra depicted that extracted crystal was pure AGL. It is one of the novel approaches to isolating pure AGL crystal in a moderately polar solvent (Ethyl acetate) by elevating the Hildebrand solubility parameter despite using polar solvents. AGL crystal was obtained from Direct Soxhlet extraction by Ethyl acetate. It is a single-step and more economical method. It can be easily transformed into a pilot or industrial setup to extract Pure AGL.

Let $$C^2[0, 1]$$ be the Banach space of all functions that have continuous derivatives $$f'$$ and $$f''$$ on the closed interval [0, 1], equipped with norm $$\Vert f\Vert = |f(0)| + |f'(0)| + \Vert f''\Vert _{\infty }$$ , where $$\Vert \cdot \Vert _{\infty }$$ is the usual supremum norm. In this paper, we characterize projections on $$C^2[0, 1]$$ that can be written as convex combination of two surjective linear isometries. We also find out the structure of Hermitian projections and generalized bi-circular projections on $$C^2[0, 1]$$ . Finally, we discuss the relationship of these two types of projections (Hermitian and generalized bi-circular projections) with the convex combination of two isometries.

The objective of research work was to development and evaluation of curcumin-loaded mesoporous silica nanoparticles (MSN), based topical dosage form for the treatment of facial wrinkles. Curcumin was selected as a hydrophobic model drug since it has been reported as potent anti-oxidizing and as an anti-wrinkle agent. Hence curcumin drug was selected as anti-wrinkle agent for the treatment of wrinkles. The MSN were prepared with tetraethyl ortho silicate and cetyltrimethyl ammonium bromide (as surfactant). The prepared MSN were characterized by using particle size analysis, scanning electron microscope, Xrd, FTIR and porosimetry. The MSN was found to be biocompatible chemically & thermally stable nanoparticles. The curcumin extract was loaded into MSN and incorporated into cream. In-vitro release study of curcumin-loaded MSN system was compared with marketed formulation and was found the curcumin-loaded mesoporous silica nanoparticles (MSN) showed good antioxidant activity and batter % cumulative drug release. The % cumulative drug release of curcumin-loaded MSN was found to be 88% at pH 5.5 and 85% at pH 7.4 respectively. Revealed that after incorporation of curcumin into MSN, the drug release rate was found increased. The properties of curcumin-loaded MSN strongly advocate its good feature for delivery of anti-wrinkles drug. The prepared curcumin-loaded MSN seem to have potential carrier for use as a topical drug delivery.

Herbal medicine has become a medicinal as well as the economic aspect of global significance. While the use of these herbal medicines has increased, there are several questions about their consistency, protection, and effectiveness in different countries. Boswellic acid (BA) is one of the active constituents obtained from plant Boswellia serrata (BS) family Burseraceae. The oleoresin gum of the plant is also known as Salai guggul, Indian olibanum, or Indian frankincense. Boswellia species comprises a variety of phytochemical components, essential oil, BA such as keto-BA, beta-BA, or acetyl keto-BA. This variety of constituents isolated from the plant using various extraction processes such as hydrodistillation, percolation, and ultraviolet-assisted extraction or solvent extraction. The active constituent has different biological activities such as antidiuretic, anticancer, anti-inflammatory, or antitumor activity. This review seeks to update information on plant BS with its medicinal uses, isolation process in the traditional or Indian system of medicine, and justify its use on modern scientific parameters.

Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to therapeutic resistance. We integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes and bulk multi-omic profiles across 11 adult IDH mutant or IDH wild-type gliomas to delineate sources of intratumoral heterogeneity. We showed that local DNA methylation disorder is associated with cell–cell DNA methylation differences, is elevated in more aggressive tumors, links with transcriptional disruption and is altered during the environmental stress response. Glioma cells under in vitro hypoxic and irradiation stress increased local DNA methylation disorder and shifted cell states. We identified a positive association between genetic and epigenetic instability that was supported in bulk longitudinally collected DNA methylation data. Increased DNA methylation disorder associated with accelerated disease progression and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work identified an epigenetically facilitated adaptive stress response process and highlights the importance of epigenetic heterogeneity in shaping therapeutic outcomes.

Objective: To developed mucoadhesive gastro-retentive films of amoxicillin trihydrate, metronidazole and famotidine by using polymers and plasticizer for eradication of H. pylori infection. Methods: The mucoadhesive gastro-retentive films of amoxicillin trihydrate, metronidazole and famotidine were prepared using solvent casting method. The optimized gastro-retentive films were characterized by using various parameters such as DSC, drug content uniformity, in vitro drug release, FTIR spectroscopy, SEM and ex-vivo drug permeation studies across the mucous membrane. The prepared mucoadhesive gastro-retentive films were evaluated with in vitro growth inhibition study and in vivo bacterial clearance study. Results: The FTIR spectra indicated that there was no any interaction between the drugs and polymer. Drugs content was found to be in the range and there was no significant change in the surface morphology of the films after under storage. The bioadhesive property of prepared films exhibited highly bioadhesive property when increased the amount of chitosan and PAA (Polyacrylic Acid) used. We found that CH-PAA IPC (Chitosan-Polyacrylic Acid Inter-polymer Complex) films exhibited greater bioadhesion. The percent of growth inhibition by using each drug such as amoxicillin, metronidazole and famotidine was found to be 51.61%, 46.59% and 34.76%, respectively whereas the combination of drugs were exhibited highest % growth inhibition. The % inhibition was found to be 81.00%. The optimized formulation CH-PAA IPC (C1P2G2) and CH film (C1G2) showed highest growth inhibition of H. pylori bacteria. The growth inhibition was found to be 96.77% and 92.26%, respectively. In vivo Bacterial Clearance Studies showed that the drugs loaded CH-PAA IPC film (C1P2G2) formulation exhibited better clearance from infection than CH film (C1G2) formulation and plain drugs solution at same doses. Drugs loaded CH-PAA IPC film formulation was found to be effective in the treatment of H. pylori infections effectively. Conclusion: The developed gastro-retentive films of amoxicillin trihydrate, metronidazole and famotidine combination could be used for batter management of mucosal ulcer disease and eradication of H. pylori bacteria.

SummaryIn coronaviridae such as SARS-CoV-2, subgenomic RNAs (sgRNA) are replicative intermediates, therefore, their abundance and structures could infer viral replication activity and severity of host infection. Here, we systematically characterized the sgRNA expression and their structural variation in 81 clinical specimens collected from symptomatic and asymptomatic individuals with a goal of assessing viral genomic signatures of disease severity. We demonstrated the highly coordinated and consistent expression of sgRNAs from individuals with robust infections that results in symptoms, and found their expression is significantly repressed in the asymptomatic infections, indicating that the ratio of sgRNAs to genomic RNA (sgRNA/gRNA) is highly correlated with the severity of the disease. Using long read sequencing technologies to characterize full-length sgRNA structures, we also observed widespread deletions in viral RNAs, and identified unique sets of deletions preferentially found primarily in symptomatic individuals, with many likely to confer changes in SARS-CoV-2 virulence and host responses. Furthermore, based on the sgRNA structures, the frequently occurred structural variants in SARS-CoV-2 genomes serves as a mechanism to further induce SARS-CoV-2 proteome complexity. Taken together, our results show that differential sgRNA expression and structural mutational burden both appear to be correlated with the clinical severity of SARS-CoV-2 infection. Longitudinally monitoring sgRNA expression and structural diversity could further guide treatment responses, testing strategies, and vaccine development.

It is estimated that up to 80% of infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are asymptomatic and asymptomatic patients can still effectively transmit the virus and cause disease. While much of the effort has been placed on decoding single nucleotide variation in SARS-CoV-2 genomes, considerably less is known about their transcript variation and any correlation with clinical severity in human hosts, as defined here by the presence or absence of symptoms. To assess viral genomic signatures of disease severity, we conducted a systematic characterization of SARS-CoV-2 transcripts and genetic variants in 81 clinical specimens collected from symptomatic and asymptomatic individuals using multi-scale transcriptomic analyses including amplicon-seq, short-read metatranscriptome and long-read Iso-seq. Here we show a highly coordinated and consistent pattern of sgRNA expression from individuals with robust SARS-CoV-2 symptomatic infection and their expression is significantly repressed in the asymptomatic infections. We also observe widespread inter- and intra-patient variants in viral RNAs, known as quasispecies frequently found in many RNA viruses. We identify unique sets of deletions preferentially found primarily in symptomatic individuals, with many likely to confer changes in SARS-CoV-2 virulence and host responses. Moreover, these frequently occurring structural variants in SARS-CoV-2 genomes serve as a mechanism to further induce SARS-CoV-2 proteome complexity. Our results indicate that differential sgRNA expression and structural mutational burden are highly correlated with the clinical severity of SARS-CoV-2 infection. Longitudinally monitoring sgRNA expression and structural diversity could further guide treatment responses, testing strategies, and vaccine development. Wong and Ngan et al. characterize the expression and structural variation of SARS-CoV-2 subgenomic RNAs (sgRNAs) in diagnostic specimens from symptomatic and asymptomatic COVID-19 patients. In a series of genomic and transcriptomic analyses, the authors observe reduced sgRNA expression and a distinct set of structural deletions in asymptomatic infections compared with symptomatic infections. Infection with SARS-CoV-2 can lead to symptoms of different severity, with some individuals remaining entirely asymptomatic but still responsible for much of the viral transmission. Here, we sought to identify markers of the severity of symptoms of SARS-CoV-2 infection, as defined by the presence or absence of symptoms. We used a combination of methods to study SARS-CoV-2 genes and their readouts, known as transcripts, in clinical samples from people with symptomatic and asymptomatic infections. We demonstrate that transcripts responsible for making viral proteins are seen at lower levels in asymptomatic infections. We also identify structural changes in the viral genes and transcripts that potentially influence the host’s response to the virus. Our study defines potential markers of symptom severity that may ultimately guide risk mitigation and testing strategies.

Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to universal therapeutic resistance. Here, we integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes, and bulk multi-omic profiles across 11 adult IDH-mutant or IDH-wild-type gliomas to delineate sources of intratumoral heterogeneity. We found that local DNA methylation instability, or epimutation burden, was elevated in more aggressive tumors, reflected intratumoral variability, linked with transcriptional disruption, and associated with environmental stress response. We show that the activation of cell-state specific transcription factors is impacted by epimutations and that loosened epigenetic control may facilitate cellular plasticity. Our analyses support that somatic copy number alterations (SCNAs) promote epigenetic instability and that SCNAs largely precede epigenetic and transcriptomic diversification during glioma evolution. We confirmed the link between genetic and epigenetic instability by analyzing larger cohorts of bulk longitudinally collected and spatially separated DNA methylation data. Increased DNA methylation instability was associated with accelerated disease progression, and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work provides an integrative framework to better understand glioma evolution and highlights the importance of epigenetic heterogeneity in shaping therapeutic response.

The genomes of multicellular organisms are extensively folded into 3D chromosome territories within the nucleus1. Advanced 3D genome-mapping methods that combine proximity ligation and high-throughput sequencing (such as chromosome conformation capture, Hi-C)2, and chromatin immunoprecipitation techniques (such as chromatin interaction analysis by paired-end tag sequencing, ChIA-PET)3, have revealed topologically associating domains4 with frequent chromatin contacts, and have identified chromatin loops mediated by specific protein factors for insulation and regulation of transcription5–7. However, these methods rely on pairwise proximity ligation and reflect population-level views, and thus cannot reveal the detailed nature of chromatin interactions. Although single-cell Hi-C8 potentially overcomes this issue, this method may be limited by the sparsity of data that is inherent to current single-cell assays. Recent advances in microfluidics have opened opportunities for droplet-based genomic analysis9 but this approach has not yet been adapted for chromatin interaction analysis. Here we describe a strategy for multiplex chromatin-interaction analysis via droplet-based and barcode-linked sequencing, which we name ChIA-Drop. We demonstrate the robustness of ChIA-Drop in capturing complex chromatin interactions with single-molecule precision, which has not been possible using methods based on population-level pairwise contacts. By applying ChIA-Drop to Drosophila cells, we show that chromatin topological structures predominantly consist of multiplex chromatin interactions with high heterogeneity; ChIA-Drop also reveals promoter-centred multivalent interactions, which provide topological insights into transcription. A strategy using droplet-based and barcode-linked sequencing captures multiplex chromatin interactions at single-molecule precision, and here provides topological insight into chromatin structures and transcription in Drosophila.

HYPOTHESIS We hypothesize that genomic variants including deletions, insertions, inversions, and tandem duplications beyond the changes in tumor suppressor NF2 gene affect gene expression of tumor-specific pathways in vestibular schwannomas (VS) patients with Neurofibromatosis type 2 (NF2), thus contributing to their clinical behavior. BACKGROUND Genomic variation could reconfigure transcription in NF2 transformation process. Therefore, genome-wide high-resolution characterization of structural variants (SV) landscapes in NF2 tumors can expand our understanding of the genes regulating the clinical phenotypes in NF2-associated VS. METHODS We performed whole-genome haplotype-specific structural variation analysis using synthetic linked reads generated through microfluidics-based barcoding of high molecular weight DNA followed by high-coverage Illumina paired-end whole-genome sequencing from 10 patients' tumors of different growth rates and their matching blood samples. RESULTS NF2 tumor-specific deletions and large SVs were detected and can be classified based on their association with tumor growth rates. Through detailed annotation of these mutations, we uncover common alleles affected by these deletions and large SVs that can be associated with signaling pathways implicated in cell proliferation and tumorigenesis. CONCLUSION The genomic variation landscape of NF2-related VS was investigated through whole-genome linked-read sequencing. Large SVs, in addition to deletions, were identified and may serve as modulators of clinical behavior.

Microstrip or patch antenna, have gained lot of importance over last two decades due to their various advantages like low volume, low profile configuration, which makes their easy integration with other system devices. Also microstrip antenna using defected ground plane structure gained importance as they yield compact, dual band, wideband and circular polarized response, with modified ground. The paper proposes a square microstrip antenna design backed by defected ground plane, for realizing circular polarized response. Circular polarization is obtained due to degeneration of orthogonal modes, created due to the defects in the ground. The proposed antenna on thinner Arlong substrate ( $0.016\lambda_{\mathrm{g}}$ ) yields respective axial ratio and input impedance bandwidth of 16 (0.93%) and 37 MHz (2.14%). The proposed low profile antenna realizes gain larger than 5 dBi for the frequency range of axial ratio less than 3 dB. An equivalent of the proposed configuration will find application in personal communications devices around 900 and 1800 MHz frequency spectrum.

Modified design of truncated corner square microstrip antenna fed using modified coaxial feed is presented for circularly polarized response. The corner truncation in patch yields the excitation of dual orthogonal modes whereas the use of modified coaxial feed yields input impedance matching for smaller probe length. The detailed explanations for the above modifications made in the patch on patch resonant mode frequencies and their impedances are explained. Due to optimum spacing in between the diagonal TM 10 and TM 01 modes of square patch, 55 MHz (5.92%) of axial ratio bandwidth occupying inside 236 MHz (23.84%) of input impedance bandwidth is obtained. Modified feed antenna exhibit broadside pattern across the axial ratio and impedance bandwidth with broadside gain of larger than 7 dBi. Using smaller coaxial feed length of $0.022\lambda_{\mathrm{g}}$ , antenna yields circular polarized bandwidth of greater than 5%, which is a new contribution in this paper. The proposed antenna with above antenna characteristics can be used in applications of mobile and personal communications systems.

Novel compact design of Sectoral microstrip antenna against increasing sectoral angle is presented for wideband circular polarized response. The detail study that put forward the effects of sectoral angle in patch, on orthogonal resonant modes is presented. It is noted that varying angle in Sectoral patch realizes the tuning amongst Sectoral patch TM 10 and TM 01 : modes and an optimum spacing between them realizes circular polarization. For Sectoral angle of 44°, wide band response with axial ratio bandwidth of larger than 10% is realized. The antenna exhibits broadside pattern across impedance and axial ratio bandwidth with peak broadside gain of above 6 dBi. As against regular shape microstrip antennas (circular, rectangular, triangular) using narrow slits or slot or the modified patch edges, proposed design is compact and offers larger circular polarized bandwidth. These are the new findings in the proposed study.

The circular polarized response in microstrip antenna is realized when two orthogonal modes placed nearby in their frequency, are present. This paper presents a details study to analyze the effects of slots in the ground plane and substrate layers, in realizing circular polarized response in multi-layer suspended configuration. The study is presented using FR4 and Arlong substrates. The slots in ground plane modifies the surface current lengths at patch fundamental orthogonal modes to yield optimum separation between them to realize CP response. The placement of thicker dielectric in suspended configuration further enhances the realized axial ratio bandwidth at the cost of marginal decrement in broadside antenna gain. The optimum response in terms of axial ratio bandwidth and gain is obtained using FR4 substrate in three layer suspended design employing thicker FR4 substrate in bottom layer. The realized circular polarized bandwidth here is more than 75 MHz (>7%) with broadside gain of nearly 5 dBi over the BW. The proposed simpler design can find usage in mobile communication systems which are operating in 1000 MHz frequency spectrum.

Detailed investigation into the orthogonal mode response of the triangular microstrip antenna against increasing angle is presented. With an offset feed position, angle changes the separation between TM10 and TM01 modes in triangular patch. The optimum spacing between two modes against varying angles yields circular polarized response. For 48° angle right-hand circular polarized response is obtained whereas with 72° angle, antenna exhibits left-hand circular polarization characteristics. In both the responses, triangular antennas yield axial ratio bandwidth of above 5% with polar radiation pattern showing maximum in broadside direction with peak co-polar gain of above 7 dBi. With realized antenna characteristics proposed antennas can be useful in application of mobile communication systems.

Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to universal therapeutic resistance. Here, we integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes, and bulk multi-omic profiles across 11 adult IDH-mutant or IDH-wild-type gliomas to delineate sources of intratumoral heterogeneity. We found that local DNA methylation instability, or epimutation burden, was elevated in more aggressive tumors, reflected intratumoral variability, linked with transcriptional disruption, and associated with environmental stress response. We show that the activation of cell-state specific transcription factors is impacted by epimutations and that loosened epigenetic control may facilitate cellular plasticity. We validated the impact that the common environmental stressor hypoxia has on the epigenetic stability and shifts in cell states through perturbation-based in vitro experiments coupled with single-cell genomics. Our analyses support that glioma cells under stress hijack epigenetic mechanisms that regulate cell state transitions to overcome challenges posed by nutrient-poor microenvironments and therapeutic insults. We confirmed the link between cellular stress and epigenetic instability by analyzing larger cohorts of bulk longitudinally collected and spatially separated DNA methylation data. Increased DNA methylation instability was associated with accelerated disease progression, and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work provides an integrative framework to better understand glioma evolution and highlights the importance of epigenetic heterogeneity in shaping therapeutic response. Citation Format: Kevin C. Johnson, Kevin J. Anderson, Elise T. Courtois, Amit D. Gujar, Floris P. Barthel, Frederick S. Varn, Diane Luo, Martine Seignon, Eunhee Yi, Hoon Kim, Marcos R. Estecio, Ming Tang, Nicholas E. Navin, Rahul Maurya, Chew Yee Ngan, Niels Verburg, Philip C. De Witt Hamer, Ketan Bulsara, Michael L. Samuels, Sunit Das, Paul Robson, Roel G. Verhaak. Single-cell multimodal glioma analyses reveal epigenetic regulators of cellular plasticity and environmental stress response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2084.

Extrachromosomal, circular DNA (ecDNA) is emerging as a prevalent yet less characterized oncogenic alteration in cancer genomes. We leverage ChIA-PET and ChIA-Drop chromatin interaction assays to characterize genome-wide ecDNA-mediated chromatin contacts that impact transcriptional programs in cancers. ecDNAs in glioblastoma patient-derived neurosphere and prostate cancer cell cultures are marked by widespread intra-ecDNA and genome-wide chromosomal interactions. ecDNA-chromatin contact foci are characterized by broad and high-level H3K27ac signals converging predominantly on chromosomal genes of increased expression levels. Prostate cancer cells harboring synthetic ecDNA circles composed of characterized enhancers result in the genome-wide activation of chromosomal gene transcription. Deciphering the chromosomal targets of ecDNAs at single-molecule resolution reveals an association with actively expressed oncogenes spatially clustered within ecDNA-directed interaction networks. Our results suggest that ecDNA can function as mobile transcriptional enhancers to promote tumor progression and manifest a potential synthetic aneuploidy mechanism of transcription control in cancer.

Proper utilization of the unused spectrum hole facilitates the expanding necessity of the elevated data rate in the upcoming 5th Generation (5G) wireless communication technology. Energy detection is a widely worked technique to fulfill this requirement with minimal time, cost, and efforts. With this motivation, this work develops an analytical framework to analyze the functioning of an energy detector (ED) based cognitive radio (CR) system over a composite fading distribution, characterized by α - μ /Inverse-Gamma (I-Gamma) composite fading channel. To begin with, closed-form expressions for the probability density function (PDF) are developed for single-input single-output (SISO) and single-input multiple-output (SIMO) channels. Exploiting these expressions, analytical results for the average probability of detection (PD) and the average area under the receiver operating characteristic curve (AUC) are obtained. Further, the breakdown is extended in determining average PD under high and very low signal-to-noise ratio (SNR) regime. Finally, the results are utilized as an application in analyzing the cooperative spectrum sensing (CSS) under different shadowing conditions. The optimization of the number of cognitive radios is carried out using the r-out-of-N voting rule. The validation of all the proposed results and their accuracy is determined using the Monte-Carlo simulations.

Extensive intra- and intertumoral heterogeneity in glioma contributes to therapeutic resistance and poor patient outcomes. Alterations to DNA methylation (DNAme) modulate epigenetic homeostasis, allowing tumor cells to sample alternative cell states to promote tumorigenesis. However, the epigenetic mechanisms that promote cellular plasticity and regulate cell states are still poorly understood. To characterize the epigenetic mechanisms underlying glioma heterogeneity we profiled 914 single-cell methylomes, 55,284 single-cell transcriptomes, and bulk whole genomes across 11 patient samples spanning initial and recurrent time points and 3 molecular subtypes delineated by IDH mutation status. Local DNAme disorder, defined as epimutation burden, was increased in tumor cells relative to nontumor cells, higher in IDH wild-type than in IDH mutant glioma and was positively associated with copy number alteration (CNA). Epimutation was positively associated with transcriptional variability and enriched at genes involved in cellular differentiation. Epimutation was also increased in the binding sites of transcription factors (TFs) associated with response to extracellular stimuli, suggesting that stochastic DNAme alterations enable cellular plasticity and diverse responses to microenvironmental stressors. Integrative clustering of DNAme and scRNAseq profiles defined stem-like and differentiated-like cell states which exhibited differences in TF activity. Stem-like cells were enriched for differentially methylated binding sites of TFs associated with hypoxia response. scDNAme and scRNAseq-derived copy number profiles were compared with bulk copy number profiles and inferred tumor phylogenies to assess how the timing of CNAs impact epigenetic instability, with results suggesting that early CNA events propagate both genetic and epigenetic heterogeneity. Bulk longitudinal data was used to validate the relationship of epigenetic instability with CNA burden as well as differentially methylated binding sites of cell stress response TFs. Our work suggests that local DNAme disorder promotes cellular plasticity and enables adaptive response to cellular stress such as hypoxia.

This research paper aims to compare the performance of various clustering and classification algorithms which are applied on the same educational dataset. Educational Data Mining (EDM) uses these algorithms to explore educational statistics to discover patterns and predictions in data that illustrate learner’s performance. Various design challenges such as accuracy, objective and functionality, and overheads when the data set is extremely large, etc., have been highlighted. The algorithms discussed here can be classified as centroid-based clustering, graph-based clustering, and various supervised classification algorithms. Further, after comparison of these algorithms, this paper aims at using the cited literature survey to determine the most suited algorithm according to the need of EDM clustering or classification. The regular search is on to understand students better and to know the patterns in which they learn to make it more efficient for them. Nowadays, many educational institutions have educational databases that can be utilized in various ways to make it effective for students but are unutilized. Powerful tools are required to get benefits from these educational databases. EDM is one of those emerging tools that analyzes the data collected from learning and teaching and then applies the techniques from machine learning and data mining for predicting student’s future behavior by learning detailed information such as student’s grades, knowledge, achievements, motivation, and attitude.

We describe a microfluidics-based strategy for genome-wide analysis of multiplex chromatin interactions with single-molecule precision. In multiplex chromatin interaction analysis (multi-ChIA), individual chromatin complexes are partitioned into droplets that contain a gel bead with unique DNA barcode, in which tethered chromatin DNA fragments are barcoded and amplified for sequencing and mapping to demarcate chromatin contacts. Thus, multi-ChIA has the unprecedented ability to uncover multiplex chromatin interactions at single-molecule level, which has been impossible using previous methods that rely on analyzing pairwise contacts via proximity ligation. We demonstrate that multiplex chromatin interactions predominantly contribute to topologically associated domains, and clusters of gene promoters and enhancers provide a fundamental topological framework for co-transcriptional regulation.

The genomes of multicellular organisms are extensively folded into 3D chromosome territories within the nucleus