Ribosomal RNA 2'-O-methylation dynamics impact cell fate decisions.

Translational regulation impacts both pluripotency maintenance and cell differentiation. To what degree the ribosome exerts control over this process remains unanswered. Accumulating evidence has demonstrated heterogeneity in ribosome composition in various organisms. 2'-O-methylation (2'-O-me) of rRNA represents an important source of heterogeneity, where site-specific alteration of methylation levels can modulate translation. Here, we examine changes in rRNA 2'-O-me during mouse brain development and tri-lineage differentiation of human embryonic stem cells (hESCs). We find distinct alterations between brain regions, as well as clear dynamics during cortex development and germ layer differentiation. We identify a methylation site impacting neuronal differentiation. Modulation of its methylation levels affects ribosome association of the fragile X mental retardation protein (FMRP) and is accompanied by an altered translation of WNT pathway-related mRNAs. Together, these data identify ribosome heterogeneity through rRNA 2'-O-me during early development and differentiation and suggest a direct role for ribosomes in regulating translation during cell fate acquisition.

FUS regulates a subset of snoRNA expression and modulates the level of rRNA modifications.

FUS is a multifunctional protein involved in many aspects of RNA metabolism, including transcription, splicing, translation, miRNA processing, and replication-dependent histone gene expression. In this work, we show that FUS depletion results in the differential expression of numerous small nucleolar RNAs (snoRNAs) that guide 2'-O methylation (2'-O-Me) and pseudouridylation of specific positions in ribosomal RNAs (rRNAs) and small nuclear RNAs (snRNAs). Using RiboMeth-seq and HydraPsiSeq for the profiling of 2'-O-Me and pseudouridylation status of rRNA species, we demonstrated considerable hypermodification at several sites in HEK293T and SH-SY5Y cells with FUS knockout (FUS KO) compared to wild-type cells. We observed a similar direction of changes in rRNA modification in differentiated SH-SY5Y cells with the FUS mutation (R495X) related to the severe disease phenotype of amyotrophic lateral sclerosis (ALS). Furthermore, the pattern of modification of some rRNA positions was correlated with the abundance of corresponding guide snoRNAs in FUS KO and FUS R495X cells. Our findings reveal a new role for FUS in modulating the modification pattern of rRNA molecules, that in turn might generate ribosome heterogeneity and constitute a fine-tuning mechanism for translation efficiency/fidelity. Therefore, we suggest that increased levels of 2'-O-Me and pseudouridylation at particular positions in rRNAs from cells with the ALS-linked FUS mutation may represent a possible new translation-related mechanism that underlies disease development and progression.

Regulation of translation by site-specific ribosomal RNA methylation.

Ribosomes are complex ribozymes that interpret genetic information by translating messenger RNA (mRNA) into proteins. Natural variation in ribosome composition has been documented in several organisms and can arise from several different sources. A key question is whether specific control over ribosome heterogeneity represents a mechanism by which translation can be regulated. We used RiboMeth-seq to demonstrate that differential 2'-O-methylation of ribosomal RNA (rRNA) represents a considerable source of ribosome heterogeneity in human cells, and that modification levels at distinct sites can change dynamically in response to upstream signaling pathways, such as MYC oncogene expression. Ablation of one prominent methylation resulted in altered translation of select mRNAs and corresponding changes in cellular phenotypes. Thus, differential rRNA 2'-O-methylation can give rise to ribosomes with specialized function. This suggests a broader mechanism where the specific regulation of rRNA modification patterns fine tunes translation.

This is not a pipe - But how harmful is electronic cigarette smoke.

This issue of the Biomedical Journal tells us about the risks of electronic cigarette smoking, variations of SARS-CoV-2 and ACE2, and how COVID-19 affects the gastrointestinal system. Moreover, we learn that cancer immunotherapy seems to work well in elderly patients, how thyroid hormones regulate noncoding RNAs in a liver tumour context, and that G6PD is a double-edged sword of redox signalling. We also discover that Perilla leaf extract could inhibit SARS-CoV-2, that artificial neural networks can diagnose COVID-19 patients and predict vaccine epitopes on the Epstein-Barr Virus, and that men and women have differential inflammatory responses to physical effort. Finally, the surgical strategies for drug-resistant epilepsy, computer-supervised double-jaw surgery, dental pulp stem cell motility, and the restitution of the brain blood supply after atherosclerotic stroke are discussed.

Guards! Guards! How innate lymphoid cells ensure local law and order.

This special issue of the Biomedical Journal is dedicated to the latest official recruits in the field of immunology: innate lymphoid cells, the tissue-resident sentinels and first responders to damage or invasion. Subsequently, we consider extracellular vesicle release during bacterial infection, how immunomodulation can avoid compromising Mycobacterium tuberculosis clearance, and how innate immunity jeopardises the organism during rheumatoid arthritis. Moreover, we ponder over the predictive value of cardiac troponin in influenza, the virtues of cashew nuts and bilirubin, as well as holes in the heart. Finally, we learn that mandibular movement during swallowing increases with the vertical dimension of occlusion, and that early controlled relaxation incisions restore the blood supply to the extremities in harlequin ichthyosis neonates.

Level up for culture models - How 3D cell culture models benefit SARS-CoV-2 research.

Welcome to a new decade and a new issue of the Biomedical Journal - casting a sorrowful look onto a year that will go down in history as a tombstone etched by the COVID-19 pandemic, but also a hopeful glance into the future, now that multiple vaccination programs against the SARS-CoV-2 virus have started. This issue is dedicated to the continuous effort by researchers all around the globe to understand and counter the pathogen, as well as to be better prepared for future threats. Therefore, we learn about the advantages of complex 3D cell culture models for studying host-virus interactions, and the disease course of COVID-19 in children. Moreover, we discover how neutralising monoclonal antibodies and peptide-based vaccines against SARS-CoV-2 are developed, and the therapeutic potentials of lopinavir/ritonavir, mesenchymal stem cells, as well as plant and algae extracts. Finally, we ponder over the lessons to be learnt from SARS-CoV and MERS, and hear about differences between nucleotide-based SARS-CoV-2 detection methods.

Don't sugar coat the COVID (only the vasculature).

This issue of the Biomedical Journal acquaints us with the compelling hypothesis that the vascular glycocalyx lies at the intersection of severe COVID-19 risk factors and damages, and the ways used by artificial intelligence to predict interactions between SARS-CoV-2 and human proteins. Furthermore, we explore the antiviral potential of valinomycin and the long list of COVID-19-related clinical trials, and learn how (not) to fix a broken femoral head. Last but not least, we get to enjoy the tale of the cellular oxygen-sensing system as well as the role of the host complement system during Leptospira infection, and learn that SARS-CoV-2 can sometimes come with a pathogenic plus one.

Pandemic number five - Latest insights into the COVID-19 crisis.

About nine months after the emergence of SARS-CoV-2, this special issue of the Biomedical Journal takes stock of its evolution into a pandemic. We acquire an elaborate overview of the history and virology of SARS-CoV-2, the epidemiology of COVID-19, and the development of therapies and vaccines, based on useful tools such as a pseudovirus system, artificial intelligence, and repurposing of existing drugs. Moreover, we learn about a potential link between COVID-19 and oral health, and some of the strategies that allowed Taiwan to handle the outbreak exceptionally well, including a COVID-19 biobank establishment, online tools for contact tracing, and the efficient management of emergency departments.

Protecting the blossoming brain - Neurocritical care in children.

This special issue of the Biomedical Journal is entirely dedicated to the latest updates regarding the medical efforts to preserve the fragile young brain after injury. Thereby, we learn about symptoms and diseases such as different forms of epilepsy, acute encephalopathy, increased intracranial pressure, and posthaemorrhagic hydrocephalus, as well as about their origins, such as infection, autoimmune diseases, preterm birth, or abusive head trauma. Moreover, diagnosis and surveillance techniques are discussed, including ultrasound of the optic nerve sheath diameter and multimodal monitoring. Finally, we discover various established and emerging therapeutic approaches, comprising target temperature management, ketogenic diet, and immunomodulation.

Bargain with the tooth fairy - The savings accounts for dental stem cells.

Despite the hard times COVID-19 has imposed on us, the Biomedical Journal strives to provide fresh and compelling reading material - to be enjoyed safely from home. In this issue, we glance behind the scenes of dental stem cell preservation for potential therapeutic use, and discover that cancer cells hijack podoplanin expression to induce thrombosis. Moreover, we learn how the helicase DDX17 promotes tumour stemness, how genetic defects in meiosis and DNA repair cause premature ovarian insufficiency, and that the brain-derived neurotrophic factor is associated with several psychiatric diseases. Further accounts relate the role of miR-95-3p in colorectal cancer, the protective power of eggplants against mercury poisoning, and the predictive value of inhibin A for premature delivery. Finally, the very rare case of adenoid cystic carcinoma in the external auditory canal receives some attention, and we get to read up on how 3D imaging and modelling combines functional and aesthetic repair of cleft lip and palate cases.

Tumour travel tours - Why circulating cancer cells value company.

Welcome to the New Year and a new issue of the Biomedical Journal, where we learn that travelling with company boosts the metastatic potential of circulating tumour cells, as well as that a worm could be an excellent model to study antidiabetic drugs. In addition, we discover another pair of molecular scissors for genetic engineering, how exactly Leptospira wreaks havoc on its run through the host organism, and that hyperparathyroidism brings its own risks, but does not worsen the outcome of papillary thyroid carcinoma. Furthermore, the importance of taking into account differing beauty ideals for aesthetic surgery surveys is discussed, alongside the question how bad isolated local recurrence is in the case of HR + breast cancer. Finally, we find out that virtual colonoscopy deserves more credit, that the first medical experiment in space was all about the H-reflex, and that it is possible to survive advanced necrotising fasciitis of the face and neck.