Gingivo-buccal oral squamous cell carcinoma (OSCC-GB), an anatomical and clinical subtype of head and neck squamous cell carcinoma (HNSCC), is prevalent in regions where tobacco-chewing is common. ...Exome sequencing (n=50) and recurrence testing (n=60) reveals that some significantly and frequently altered genes are specific to OSCC-GB (USP9X, MLL4, ARID2, UNC13C and TRPM3), while some others are shared with HNSCC (for example, TP53, FAT1, CASP8, HRAS and NOTCH1). We also find new genes with recurrent amplifications (for example, DROSHA, YAP1) or homozygous deletions (for example, DDX3X) in OSCC-GB. We find a high proportion of C>G transversions among tobacco users with high numbers of mutations. Many pathways that are enriched for genomic alterations are specific to OSCC-GB. Our work reveals molecular subtypes with distinctive mutational profiles such as patients predominantly harbouring mutations in CASP8 with or without mutations in FAT1. Mean duration of disease-free survival is significantly elevated in some molecular subgroups. These findings open new avenues for biological characterization and exploration of therapies.
Histone H3.3 is an H3 variant which differs from the canonical H3.1/2 at four residues, including a serine residue at position 31 which is evolutionarily conserved. The H3.3 S31 residue is ...phosphorylated (H3.3 S31Ph) at heterochromatin regions including telomeres and pericentric repeats. However, the role of H3.3 S31Ph in these regions remains unknown. In this study, we find that H3.3 S31Ph regulates heterochromatin accessibility at telomeres during replication through regulation of H3K9/K36 histone demethylase KDM4B. In mouse embryonic stem (ES) cells, substitution of S31 with an alanine residue (H3.3 A31 -phosphorylation null mutant) results in increased KDM4B activity that removes H3K9me3 from telomeres. In contrast, substitution with a glutamic acid (H3.3 E31, mimics S31 phosphorylation) inhibits KDM4B, leading to increased H3K9me3 and DNA damage at telomeres. H3.3 E31 expression also increases damage at other heterochromatin regions including the pericentric heterochromatin and Y chromosome-specific satellite DNA repeats. We propose that H3.3 S31Ph regulation of KDM4B is required to control heterochromatin accessibility of repetitive DNA and preserve chromatin integrity.
An array of oncogenic histone point mutations have been identified across a number of different cancer studies. It has been suggested that some of these mutant histones can exert their effects by ...inhibiting epigenetic writers. Here, we report that the H3.3 G34R (glycine to arginine) substitution mutation, found in paediatric gliomas, causes widespread changes in H3K9me3 and H3K36me3 by interfering with the KDM4 family of K9/K36 demethylases. Expression of a targeted single-copy of H3.3 G34R at endogenous levels induced chromatin alterations that were comparable to a KDM4 A/B/C triple-knockout. We find that H3.3 G34R preferentially binds KDM4 while simultaneously inhibiting its enzymatic activity, demonstrating that histone mutations can act through inhibition of epigenetic erasers. These results suggest that histone point mutations can exert their effects through interactions with a range of epigenetic readers, writers and erasers.
Accurate and rapid detection and isolation become indispensable to restrict the spread of COVID-19. Since the start of COVID-19 pandemic in December 2019, many indisposal diagnostic tools are being ...developed incessantly. Out of all presently used tools, the gold standard rRT- PCR tool having very high sensitivity and specificity is a time consuming complicated molecular technique having requirements of special expensive equipment. Here, the main focus of this work is to develop rapid disposal paper capacitance sensor having simple and easy detection. We discovered a strong interaction between limonin and Spike-glycoprotein of SARS-COV-2 in comparison to its interaction with other similar viruses such as HCOV-OC43, HCOV-NL63, HCOV-HKU1, Influenza B and A viruses. The antibody free capacitive sensor having comb electrode structure was fabricated on whatman paper with drop coating of limonin (extracted using green method from pomelo seeds) and calibrated with known swab samples. The Blind test with unknown swab samples shows high sensitivity of 91.5% and high specificity of 88.37%. Requiring low sample volume and detection time and using biodegradable materials in the sensor fabrication assure the potential application as a point of care disposal diagnostic tool.
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•A rapid COVID-19 detection kit based on capacitive sensor based has been developed.•Limonin extracted from plant seeds has been used as sensing material.•The sensor exhibited high sensitivity of 91.5%(clinical) with high specificity of 88.37%.•Detection time for the sensor is ∼182s with sample volume requirement of 10 μL.•This paper-based sensor assures inexpensive, easy, onsite detection of COVID-19.
Highly improved catalytic reductive degradation of different organic dyes, in the presence of excess NaBH
4
over Au/CeO
2
-TiO
2
nano-hybrid as the catalyst is reported in this study. CeO
2
-TiO
2
...nanocomposite was prepared by a facile co-precipitation method using ultra-high dilute aqueous solutions. Small amount of Au (only 1 wt%) was loaded onto the nanocomposite material by deposition-precipitation with urea (DPU) method to fabricate the ternary Au/CeO
2
-TiO
2
nano-hybrid. The catalysts were characterized by the representative techniques like XRD, BET surface area, ICP-AES, UV-Vis diffuse reflectance spectroscopy, TEM and XPS. The Au/CeO
2
-TiO
2
nano-hybrid along with NaBH
4
exhibited remarkable catalytic activities towards all the probed dyes, namely Methylene Blue, Methyl Orange, Congo Red, Rhodamine B and Malachite Green, with a degradation efficiency of ∼100% in a short reaction time. The degradation reaction followed pseudo-first-order kinetics with respect to the concentration of the dye. Different parameters that affect the rate of the reaction are discussed. A plausible mechanism for methylene blue degradation has also been proposed.
Graphical Abstract
Nanosized Gold particles stabilized on CeO
2
-TiO
2
nanocomposite exhibits tremendous catalytic activity in the reductive degradation of various organic dyes with Au/CeO
2
-TiO
2
nanocatalyst possesses good stability and reusability which reveals the potential for its practical applications.
Engineering the band gap of semiconductors is often crucial in the quest for developing new and advanced technologies. In this report, the implication of graphene on the band gap optimization of ...tungsten trioxide (WO
3
) is discussed. Simple one-step sol–gel process was followed to anchor WO
3
nanoparticles in graphene. Graphene induces a redshift in the band gap of WO
3
. Band gap narrowing of 6.60% is observed for 7 wt% graphene-tethered WO
3
. Interestingly, a profound difference is observed in estimating the band gap energy values following the usual Tauc equation. Our observation suggests that the differential form of Tauc equation is better suited to determine the band gap energy of inorganic semiconductors than the typical extrapolation method.
MicroRNAs (miRNAs) are critical regulators of transcriptional and post-transcriptional gene silencing, which are involved in multiple developmental processes in many organisms. Apart from miRNAs, ...mouse germ cells express another type of small RNA, piwi-interacting RNAs (piRNAs). Although it has been clear that piRNAs play a role in repression of retrotransposons during spermatogenesis, the function of miRNA in mouse germ cells has been unclear.
In this study, we first revealed the expression pattern of miRNAs by using a real-time PCR-based 220-plex miRNA expression profiling method. During development of germ cells, miR-17-92 cluster, which is thought to promote cell cycling, and the ES cell-specific cluster encoding miR-290 to -295 (miR-290-295 cluster) were highly expressed in primordial germ cells (PGCs) and spermatogonia. A set of miRNAs was developmentally regulated. We next analysed function of miRNA biogenesis in germ cell development by using conditional Dicer-knockout mice in which Dicer gene was deleted specifically in the germ cells. Dicer-deleted PGCs and spermatogonia exhibited poor proliferation. Retrotransposon activity was unexpectedly suppressed in Dicer-deleted PGCs, but not affected in the spermatogonia. In Dicer-deleted testis, spermatogenesis was retarded at an early stage when proliferation and/or early differentiation. Additionally, we analysed spermatogenesis in conditional Argonaute2-deficient mice. In contrast to Dicer-deficient testis, spermatogenesis in Argonaute2-deficient testis was indistinguishable from that in wild type.
These results illustrate that miRNAs are important for the proliferation of PGCs and spermatogonia, but dispensable for the repression of retrotransposons in developing germ cells. Consistently, miRNAs promoting cell cycling are highly expressed in PGCs and spermatogonia. Furthermore, based on normal spermatogenesis in Argonaute2-deficient testis, the critical function of Dicer in spermatogenesis is independent of Argonaute2.
The mechanisms underlying microRNA (miRNA) disruption in human disease are poorly understood. In cancer cells, the transcriptional silencing of tumor suppressor genes by CpG island promoter ...hypermethylation has emerged as a common hallmark. We wondered if the same epigenetic disruption can "hit" miRNAs in transformed cells. To address this issue, we have used cancer cells genetically deficient for the DNA methyltransferase enzymes in combination with a miRNA expression profiling. We have observed that DNA hypomethylation induces a release of miRNA silencing in cancer cells. One of the main targets is miRNA-124a, which undergoes transcriptional inactivation by CpG island hypermethylation in human tumors from different cell types. Interestingly, we functionally link the epigenetic loss of miRNA-124a with the activation of cyclin D kinase 6, a bona fide oncogenic factor, and the phosphorylation of the retinoblastoma, a tumor suppressor gene.
It is hypothesized that same driver gene mutations should be present in both oral leukoplakia and cancer tissues. So, we attempted to find out mutations at one of the driver genes, CASP8, in cancer ...and adjacent leukoplakia tissues. Patients (n = 27), affected by both of cancer and adjacent leukoplakia, were recruited for the study. Blood and tissue DNA samples were used to identify somatic mutations at CASP8 by next generation sequencing method. In total, 56% (15 out of 27) cancer and 30% (8 out of 27) leukoplakia tissues had CASP8 somatic mutations. In 8 patients, both cancer and adjacent leukoplakia tissues, located within 2-5 cm of tumor sites, had identical somatic mutations. But, in 7 patients, cancer samples had somatic mutations but none of the leukoplakia tissues, located beyond 5cm of tumor sites, had somatic mutations. Mutated allele frequencies at CASP8 were found to be more in cancer compared to adjacent leukoplakia tissues. This study provides mutational evidence that oral cancer might have progressed from previously grown leukoplakia lesion. Leukoplakia tissues, located beyond 5cm of cancer sites, were free from mutation. The study implies that CASP8 mutation could be one of the signatures for some of the leukoplakia to progress to oral cancer.
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