Inhibiting arginine methylation as a tool to investigate cross-talk with methylation and acetylation post-translational modifications in a glioblastoma cell line

Glioblastomas (GBM) are the most common grade 4 brain tumours; patients have very poor prognosis with an average survival of 15 months after diagnosis. Novel research lines have begun to explore aberrant protein arginine methylation (ArgMe) as a possible therapeutic target in GBM and ArgMe inhibitors are currently in clinical trials. Enzymes known as protein arginine methyltransferases (PRMT1-9) can lead to mono-or di-ArgMe, and in the latter case symmetric or asymmetric dimethylation (SDMA and ADMA, respectively). Using the most common GBM cell line, we have profiled the expression of PRMTs, used ArgMe inhibitors as tools to investigate post-translational modifications cross-talk and measured the effect of ArgMe inhibitors on cell viability. We have identified novel SDMA events upon inhibition of ADMA in GBM cells and spheroids. We have observed cross-talk between ADMA and lysine acetylation in GBM cells and platelets. Treatment of GBM cells with furamidine, a PRMT1 inhibitor, reduces cell viability in 2D and 3D models. These data provide new molecular understanding of a disease with unmet clinical needs

Samanantar: The Largest Publicly Available Parallel Corpora Collection for 11 Indic Languages

We present Samanantar, the largest publicly available parallel corpora collection for Indic languages. The collection contains a total of 49.7 million sentence pairs between English and 11 Indic languages (from two language families). Specifically, we compile 12.4 million sentence pairs from existing, publicly-available parallel corpora, and additionally mine 37.4 million sentence pairs from the web, resulting in a 4x increase. We mine the parallel sentences from the web by combining many corpora, tools, and methods: (a) web-crawled monolingual corpora, (b) document OCR for extracting sentences from scanned documents, (c) multilingual representation models for aligning sentences, and (d) approximate nearest neighbor search for searching in a large collection of sentences. Human evaluation of samples from the newly mined corpora validate the high quality of the parallel sentences across 11 languages. Further, we extract 83.4 million sentence pairs between all 55 Indic language pairs from the English-centric parallel corpus using English as the pivot language. We trained multilingual NMT models spanning all these languages on Samanantar, which outperform existing models and baselines on publicly available benchmarks, such as FLORES, establishing the utility of Samanantar. Our data and models are available publicly at https://indicnlp.ai4bharat.org/samanantar/ and we hope they will help advance research in NMT and multilingual NLP for Indic languages.Comment: Accepted to the Transactions of the Association for Computational Linguistics (TACL

Investigating the effects of arginine methylation inhibitors on microdissected brain tumour biopsies maintained in a miniaturised perfusion system

Arginine methylation is a post-translational modification that consists of the transfer of one or two methyl (CH3) groups to arginine residues in proteins. Several types of arginine methylation occur, namely monomethylation, symmetric dimethylation and asymmetric dimethylation, which are catalysed by different protein arginine methyltransferases (PRMTs). Inhibitors of PRMTs have recently entered clinical trials to target several types of cancer, including gliomas (NCT04089449). People with glioblastoma (GBM), the most aggressive form of brain tumour, are among those with the poorest quality of life and survival of anyone diagnosed with cancer. There is currently a lack of (pre)clinical research on the possible application of PRMT inhibitors to target brain tumours. Here, we set out to investigate the effects of clinically-relevant PRMT inhibitors on GBM biopsies. We present a new, low-cost, easy to fabricate perfusion device that can maintain GBM tissue in a viable condition for at least eight days post-surgical resection. Theminiaturised perfusion device enables the treatment of GBM tissue with PRMT inhibitors ex vivo, and we observed a two-fold increase in apoptosis in treated samples compared to parallel control experiments. Mechanistically, we show thousands of differentially expressed genes after treatment, and changes in the type of arginine methylation of the RNA binding protein FUS that are consistent with hundreds of differential gene splicing events. This is the first time that cross-talk between different types of arginine methylation has been observed in clinical samples after treatment with PRMT inhibitors

Posterior Cranial Fossa Meningioma Causing Tonsillar Herniation and Giant Cervicothoracic Syringomyelia, Case Report and Review of Literature

Abstract Background Syringomyelia is a fluid-filled cyst within the spinal cord and usually associated with Arnold-Chiari malformation. Posterior cranial fossa tumours are a rare cause of tonsillar herniation and secondary syringomyelia. Case Presentation: We report a rare case of a 56-year-old female with posterior cranial meningioma and secondary syringomyelia, admitted with headache, nausea, vomiting, and ataxic gait. MRI demonstrated a large posterior fossa lesion causing early ventriculomegaly and syrinx within the upper spinal cord extending from the hindbrain inferiorly to the level of T8. She underwent a posterior fossa craniectomy with left C1 hemilaminectomy and complete excision of the tumour. In 6 months following her procedure, MRI scan showed a significant reduction in the calibre of the syringomyelia throughout its length and there was a significant improvement in symptoms. Literature review: A PubMed literature search was carried out with keywords: “syringomyelia”, “posterior fossa” and “tumour”. 120 articles were reviewed. The inclusion criteria for this study was posterior fossa meningioma causing syrinx formation. A total of 9 isolated similar cases were identified. Discussion Tonsillar herniation and syringomyelia secondary to posterior cranial fossa meningioma are rare. The alteration in the dynamic flow of CSF is likely to be the cause for the formation and enlargement of the syrinx. Conclusion Although the pathophysiology of syrinx formation is still poorly understood, the alteration of CSF dynamic has been implicated, but a common unifying cause appears to be increased transcranial difference in intracranial pressure across the foramen magnum causing tonsillar herniation, irrespective of location in the posterior fossa. Posterior fossa craniotomy and excision of the lesion is the mainstay treatment.</jats:p

A profile of arginine methyltransferase receptors in two immortal glioblastoma cell lines: the precursor to a novel target?

Abstract Background Glioblastoma is a deadly disease with a median survival of 15 months after treatment. While maximal safe surgical resection and adjuvant chemoradiotherapy continues to be the mainstay of treatment, glioblastoma demostrates a remarkably heterogeneous molecular profile, and there is a drive to discover further chemotherapeutic targets that can effectively augment current multimodal therapy. Introduction Post-translational modification of proteins plays a key role in maintenance of regulatory cell networks, and protein arginine methyltransferases (PRMT) are one of the enzymes involved in symmetric and asymmetric methylation of various proteins. We aim to demonstrate the entire range of PRMT proteins expressed in two different glioblastoma cell lines (U87MG and U251) in order to elucidate a consistency in expression of these proteins across cell lines. Methods Cells from 2 different glioblastoma cell lines (U87MG and U251) were cultured and lysed using standard aseptic techniques. Protein profiling was done using SDS-PAGE electrophoresis with a molecular weight marker as the reference and all primary antibodies to various PRMTs (1–10) and respective secondary antibodies. Membranes were visualised with a chemiluminescent protocol. Experiments were repeated in order to reduce bias. Conclusion It was clearly seen that in both cell lines there is a strong tendency for PRMT5 expression and relative under-expresssion of PRMT 9/10. In addition, however, there are varying expressions of other PRMTs as well. We aim to further explore this to improve the strength of this correlation. </jats:sec

A solar tracker integrated microreactor for real-time sunlight induced ketene formation and API synthesis

Catalyst free, newly fabricated solar panel reactor for the fluctuating light condition, 20 new entry, gram scale synthesis, safe and green process, sun-light is energy source.</jats:p