Architects and Partners: The Dual Roles of Non-coding RNAs in Gene Fusion Events.

Extensive research into gene fusions in cancer and other diseases has led to the discovery of novel biomarkers and therapeutic targets. Concurrently, various bioinformatics tools have been developed for fusion detection in RNA sequencing data, which, in the age of increasing affordability of sequencing, have delivered a large-scale identification of transcriptomic abnormalities. Historically, the focus of fusion transcript research was predominantly on coding RNAs and their resultant proteins, often overlooking non-coding RNAs (ncRNAs).

Harnessing genomic technologies for one health solutions in the tropics.

Background: The targeted application of cutting-edge high-throughput molecular data technologies provides an enormous opportunity to address key health, economic and environmental issues in the tropics within the One Health framework. The Earth's tropical regions are projected to contain > 50% of the world's population by 2050 coupled with 80% of its biodiversity however these regions are relatively less developed economically, with agricultural productivity substantially lower than temperate zones, a large percentage of its population having limited health care options and much of its biodiversity understudied and undescribed. The generation of high-throughput molecular data and bespoke bioinformatics capability to address these unique challenges offers an enormous opportunity for people living in the tropics.

Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability.

Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted once-daily oral dosing potential due to improvements in its metabolic stability and its pharmacokinetic properties in preclinical animal species.

SpliceWiz: interactive analysis and visualization of alternative splicing in R.

Alternative splicing (AS) is a crucial mechanism for regulating gene expression and isoform diversity in eukaryotes. However, the analysis and visualization of AS events from RNA sequencing data remains challenging. Most tools require a certain level of computer literacy and the available means of visualizing AS events, such as coverage and sashimi plots, have limitations and can be misleading.

Identifying cancer driver genes in individual tumours.

Cancer is a heterogeneous disease with a strong genetic component making it suitable for precision medicine approaches aimed at identifying the underlying molecular drivers within a tumour. Large scale population-level cancer sequencing consortia have identified many actionable mutations common across both cancer types and sub-types, resulting in an increasing number of successful precision medicine programs. Nonetheless, such approaches fail to consider the effects of mutations unique to an individual patient and may miss rare driver mutations, necessitating personalised approaches to driver-gene prioritisation.

Discovery of a Druggable, Cryptic Pocket in SARS-CoV-2 nsp16 Using Allosteric Inhibitors.

A collaborative, open-science team undertook discovery of novel small molecule inhibitors of the SARS-CoV-2 nsp16-nsp10 2'--methyltransferase using a high throughput screening approach with the potential to reveal new inhibition strategies. This screen yielded compound , a ligand possessing an electron-deficient double bond, as an inhibitor of SARS-CoV-2 nsp16 activity. Surprisingly, X-ray crystal structures revealed that covalently binds within a previously unrecognized cryptic pocket near the -adenosylmethionine binding cleft in a manner that prevents occupation by -adenosylmethionine.

The application of long-read sequencing in clinical settings.

Long-read DNA sequencing technologies have been rapidly evolving in recent years, and their ability to assess large and complex regions of the genome makes them ideal for clinical applications in molecular diagnosis and therapy selection, thereby providing a valuable tool for precision medicine. In the third-generation sequencing duopoly, Oxford Nanopore Technologies and Pacific Biosciences work towards increasing the accuracy, throughput, and portability of long-read sequencing methods while trying to keep costs low. These trades have made long-read sequencing an attractive tool for use in research and clinical settings.

A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations.

Purpose: To determine the safety and efficacy of PARP plus PD-L1 inhibition (olaparib + durvalumab, O + D) in patients with advanced solid, predominantly rare cancers harbouring homologous recombination repair (HRR) defects.

Patients And Methods: In total, 48 patients were treated with O + D, 16 with BRCA1/2 alterations (group 1) and 32 with other select HRR alterations (group 2). Overall, 32 (66%) patients had rare or less common cancers.

Accelerating antiviral drug discovery: lessons from COVID-19.

During the coronavirus disease 2019 (COVID-19) pandemic, a wave of rapid and collaborative drug discovery efforts took place in academia and industry, culminating in several therapeutics being discovered, approved and deployed in a 2-year time frame. This article summarizes the collective experience of several pharmaceutical companies and academic collaborations that were active in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral discovery. We outline our opinions and experiences on key stages in the small-molecule drug discovery process: target selection, medicinal chemistry, antiviral assays, animal efficacy and attempts to pre-empt resistance.

Single-cell and long-read sequencing to enhance modelling of splicing and cell-fate determination.

Single-cell sequencing technologies have revolutionised the life sciences and biomedical research. Single-cell sequencing provides high-resolution data on cell heterogeneity, allowing high-fidelity cell type identification, and lineage tracking. Computational algorithms and mathematical models have been developed to make sense of the data, compensate for errors and simulate the biological processes, which has led to breakthroughs in our understanding of cell differentiation, cell-fate determination and tissue cell composition.

Network-Based and Machine-Learning Approaches Identify Diagnostic and Prognostic Models for EMT-Type Gastric Tumors.

The microsatellite stable/epithelial-mesenchymal transition (MSS/EMT) subtype of gastric cancer represents a highly aggressive class of tumors associated with low rates of survival and considerably high probabilities of recurrence. In the era of precision medicine, the accurate and prompt diagnosis of tumors of this subtype is of vital importance. In this study, we used Weighted Gene Co-expression Network Analysis (WGCNA) to identify a differentially expressed co-expression module of mRNAs in EMT-type gastric tumors.

Overview of Computational and Experimental Methods to Identify Tissue-Specific MicroRNA Targets.

As ubiquitous posttranscriptional regulators of gene expression, microRNAs (miRNAs) play key roles in cell physiology and function across taxa. In the last two decades, we have gained a good understanding about miRNA biogenesis pathways, modes of action, and consequences of miRNA-mediated gene regulation. More recently, research has focused on exploring causes for miRNA dysregulation, miRNA-mediated crosstalk between genes and signaling pathways, and the role of miRNAs in disease.

Towards resolution of the intron retention paradox in breast cancer.

Background: After many years of neglect in the field of alternative splicing, the importance of intron retention (IR) in cancer has come into focus following landmark discoveries of aberrant IR patterns in cancer. Many solid and liquid tumours are associated with drastic increases in IR, and such patterns have been pursued as both biomarkers and therapeutic targets. Paradoxically, breast cancer (BrCa) is the only tumour type in which IR is reduced compared to adjacent normal breast tissue.

Recent advances in cancer fusion transcript detection.

Extensive investigation of gene fusions in cancer has led to the discovery of novel biomarkers and therapeutic targets. To date, most studies have neglected chromosomal rearrangement-independent fusion transcripts and complex fusion structures such as double or triple-hop fusions, and fusion-circRNAs. In this review, we untangle fusion-related terminology and propose a classification system involving both gene and transcript fusions.

Characterization of a KDM5 small molecule inhibitor with antiviral activity against hepatitis B virus.

Chronic hepatitis B (CHB) is a global health care challenge and a major cause of liver disease. To find new therapeutic avenues with a potential to functionally cure chronic Hepatitis B virus (HBV) infection, we performed a focused screen of epigenetic modifiers to identify potential inhibitors of replication or gene expression. From this work we identified isonicotinic acid inhibitors of the histone lysine demethylase 5 (KDM5) with potent anti-HBV activity.

The Role of MicroRNAs in Cancer Biology and Therapy from a Systems Biology Perspective.

Since the discovery of microRNAs (miRNAs) in Caenorhabditis elegans, our understanding of their cellular function has progressed continuously. Today, we have a good understanding of miRNA-mediated gene regulation, miRNA-mediated cross talk between genes including competing endogenous RNAs, and miRNA-mediated signaling transduction both in normal human physiology and in diseases.Besides, these noncoding RNAs have shown their value for clinical applications, especially in an oncological context.

Discovery and development of oseltamivir at Gilead Sciences.

John Martin's untimely death in March 2021 was a huge loss for us personally, Gilead Sciences, the company he built over 30 years and the scientific community concerned with antiviral therapies. We wish to honor John's legacy by retelling the discovery and history of Tamiflu and his contributions to it. Without his vision, persistence, and keen eye for opportunities, Tamiflu would not exist and Gilead's path would not have been the same.

Intron retention: importance, challenges, and opportunities.

Recent landmark discoveries have underpinned the physiological importance of intron retention (IR) across multiple domains of life and revealed an unexpected breath of functions in a large variety of biological processes. Despite significant progress in the field, some challenges remain. Once solved, opportunities will arise for discovering more functions of IR.

The Fusion of and Arises from a -Splicing Event in Normal and Transformed Human Cells.

Chimeric RNAs are often associated with chromosomal rearrangements in cancer. In addition, they are also widely detected in normal tissues, contributing to transcriptomic complexity. Despite their prevalence, little is known about the characteristics and functions of chimeric RNAs.

Structure-function relationships explain CTCF zinc finger mutation phenotypes in cancer.

CCCTC-binding factor (CTCF) plays fundamental roles in transcriptional regulation and chromatin architecture maintenance. CTCF is also a tumour suppressor frequently mutated in cancer, however, the structural and functional impact of mutations have not been examined. We performed molecular and structural characterisation of five cancer-specific CTCF missense zinc finger (ZF) mutations occurring within key intra- and inter-ZF residues.

An atomistic model of the coronavirus replication-transcription complex as a hexamer assembled around nsp15.

The SARS-CoV-2 replication-transcription complex is an assembly of nonstructural viral proteins that collectively act to reproduce the viral genome and generate mRNA transcripts. While the structures of the individual proteins involved are known, how they assemble into a functioning superstructure is not. Applying molecular modeling tools, including protein-protein docking, to the available structures of nsp7-nsp16 and the nucleocapsid, we have constructed an atomistic model of how these proteins associate.

Prospects and challenges of cancer systems medicine: from genes to disease networks.

It is becoming evident that holistic perspectives toward cancer are crucial in deciphering the overwhelming complexity of tumors. Single-layer analysis of genome-wide data has greatly contributed to our understanding of cellular systems and their perturbations. However, fundamental gaps in our knowledge persist and hamper the design of effective interventions.

CTCF as a regulator of alternative splicing: new tricks for an old player.

Three decades of research have established the CCCTC-binding factor (CTCF) as a ubiquitously expressed chromatin organizing factor and master regulator of gene expression. A new role for CTCF as a regulator of alternative splicing (AS) has now emerged. CTCF has been directly and indirectly linked to the modulation of AS at the individual transcript and at the transcriptome-wide level.

Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia Patients.

Vast transcriptomics and epigenomics changes are characteristic of human cancers, including leukaemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken.