Fungi - an Amalgam of Toxins and Antibiotics: a Mini- Review

Fungi are eukaryotes with many functions. Earlier, fungi were classified in the plant kingdom but were later classified as a separate kingdom due to their unique cell walls. Fungi are heterotrophs like animals and are more closely related to animals. The perception of fungi is inconspicuous due to their small sizes and their ability to grow symbiotically in plants, animals, other fungi, and parasites. Fungi are used for their nutrition, fermentation potential, and bactericidal potential. However, fungi are also toxic due to certain bioactive compounds known as mycotoxins. Candida and Aspergillus are invasive species that contribute to a high percentage of mycoses in oncological and haematological patients. The mortality rate due to invasive aspergillosis and candidiasis is high, at 4% and 2%, respectively. In the agriculture sector, a significant contributor to damage to crops globally is the invasion of filamentous fungi. Fungi invasion destroys over 125 million tons of wheat, rice, soybeans, potatoes, and maize annually. If prevented, 600 million people may be fed. Therefore, it is vital to consider the dual role of fungi, therapeutic, and pathogenic

Structure-based screening of DNA GyraseB inhibitors for therapeutic applications in tuberculosis : a pharmacoinformatics study

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB) and considered as serious public health concern worldwide which kills approximately five thousand people every day. Therefore, TB drug development efforts are in gigantic need for identification of new potential chemical agents to eradicate TB from the society. The bacterial DNA gyrase B (GyrB) protein as an experimentally widely accepted effective drug target for the development of TB chemotherapeutics. In the present study, advanced pharmacoinformatics approaches were used to screen the Mcule database against the GyrB protein. Based on a number of chemometric parameters, five molecules were found to be crucial to inhibit the GyrB. A number of molecular binding interactions between the proposed inhibitors and important active site residues of GyrB were observed. The predicted drug-likeness properties of all molecules were indicated that compounds possess characteristics to be the drug-like candidates. The dynamic nature of each molecule was explored through the molecular dynamics (MD) simulation study. Various analyzing parameters from MD simulation trajectory have suggested rationality of the molecules to be potential GyrB inhibitor. Moreover, the binding free energy was calculated from the entire MD simulation trajectories highlighted greater binding free energy values for all newly identified compounds also substantiated the strong binding affection towards the GyrB in comparison to the novobiocin. Therefore, the proposed molecules might be considered as potential anti-TB chemical agents for future drug discovery purposes subjected to experimental validation.The Researchers Supporting Project through King Saud University, Riyadh, Saudi Arabia.http://link.springer.com/journal/12010hj2021Chemical Patholog

The histone methyltransferase SETD2 negatively regulates cell size

Cell size varies between cell types but is tightly regulated by cell intrinsic and extrinsic mechanisms. Cell size control is important for cell function, and changes in cell size are frequently observed in cancer. Here, we uncover a role for SETD2 in regulating cell size. SETD2 is a lysine methyltransferase and a tumor suppressor protein involved in transcription, RNA processing and DNA repair. At the molecular level, SETD2 is best known for associating with RNA polymerase II through its Set2-Rbp1 interacting (SRI) domain and methylating histone H3 on lysine 36 (H3K36) during transcription. Using multiple independent perturbation strategies, we identify SETD2 as a negative regulator of global protein synthesis rates and cell size. We provide evidence that overexpression of the H3K36 demethylase KDM4A or the oncohistone H3.3K36M also increase cell size. In addition, ectopic overexpression of a decoy SRI domain increased cell size, suggesting that the relevant substrate is engaged by SETD2 via its SRI domain. These data add a central role of SETD2 in regulating cellular physiology and warrant further studies on separating the different functions of SETD2 in cancer development

The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling

BACKGROUND & AIMS: Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer-associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic.METHODS: We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, gamma-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 2'-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients.RESULTS: High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in microsatellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients.CONCLUSIONS: We found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors

Computation and visualization of fabrication artifacts

This paper proposes a novel technique to measure fabrication artifacts through direct comparison of a reference surface model with the corresponding industrial CT volume. Our technique uses the information from the surface model to locate corresponding points in the CT dataset. We then compute various comparison metrics to measure differences (fabrication artifacts) between the two datasets. The differences are presented to the user both visually as well as quantitatively. Our comparison techniques are divided into two groups, namely geometry-driven comparison techniques and visual-driven comparison techniques. The geometry-driven techniques provide an overview, while the visual-driven techniques can be used for a localized examination

Feature peeling

We present a novel rendering algorithm that analyses the ray profiles along the line of sight. The profiles are subdivided according to encountered peaks and valleys at so called transition points. The sensitivity of these transition points is calibrated via two thresholds. The slope threshold is based on the magnitude of a peak following a valley, while the peeling threshold measures the depth of the transition point relative to the neighboring rays. This technique separates the dataset into a number of feature layers. The user can scroll through the layers inspecting various features from the current view position. While our technique has been inspired by opacity peeling approach, we demonstrate that we can reveal detectable features even in the third and forth layers for both CT and MRI datasets

Graphics, Usability, and

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