Hypoxia signalling in the regulation of innate immune training

Innate immune function is shaped by prior exposures in a phenomenon often referred to as ‘memory’ or ‘training’. Diverse stimuli, ranging from pathogen-associated molecules to atherogenic lipoproteins, induce long-lasting training, impacting on future responses, even to distinct stimuli. It is now recognised that epigenetic modifications in innate immune cells, and their progenitors, underpin these sustained behavioural changes, and that rewired cellular metabolism plays a key role in facilitating such epigenetic marks. Oxygen is central to cellular metabolism, and cells exposed to hypoxia undergo profound metabolic rewiring. A central effector of these responses are the hypoxia inducible factors (or HIFs), which drive transcriptional programmes aiming to adapt cellular homeostasis, such as by increasing glycolysis. These metabolic shifts indirectly promote post-translational modification of the DNA-binding histone proteins, and also of DNA itself, which are retained even after cellular oxygen tension and metabolism normalise, chronically altering DNA accessibility and utilisation. Notably, the activity of HIFs can be induced in some normoxic circumstances, indicating their broad importance to cell biology, irrespective of oxygen tension. Some HIFs are implicated in innate immune training and hypoxia is present in many disease states, yet many questions remain about the association between hypoxia and training, both in health and disease. Moreover, it is now appreciated that cellular responses to hypoxia are mediated by non-HIF pathways, suggesting that other mechanisms of training may be possible. This review sets out to define what is already known about the topic, address gaps in our knowledge, and provide recommendations for future research.

Chemogenetic approaches to dissect the role of H2O2 in redox-dependent pathways using genetically encoded biosensors

Chemogenetic tools are recombinant enzymes that can be targeted to specific organelles and tissues. The provision or removal of the enzyme substrate permits control of its biochemical activities. Yeast-derived enzyme D-amino acid oxidase (DAAO) represents the first of its kind for a substrate-based chemogenetic approach to modulate H2O2 concentrations within cells. Combining these powerful enzymes with multiparametric imaging methods exploiting genetically encoded biosensors has opened new lines of investigations in life sciences. In recent years, the chemogenetic DAAO approach has proven beneficial to establish a new role for (patho)physiological oxidative stress on redox-dependent signaling and metabolic pathways in cultured cells and animal model systems. This mini-review covers established or emerging methods and assesses newer approaches exploiting chemogenetic tools combined with genetically encoded biosensors.

Structure-based inhibitor design and repurposing clinical drugs to target SARS-CoV-2 proteases

SARS-CoV-2, the coronavirus responsible for the current COVID-19 pandemic, encodes two proteases, 3CLpro and PLpro, two of the main antiviral research targets. Here we provide an overview of the structures and functions of 3CLpro and PLpro and examine strategies of structure-based drug designing and drug repurposing against these proteases. Rational structure-based drug design enables the generation of potent and target-specific antivirals. Drug repurposing offers an attractive prospect with an accelerated turnaround. Thus far, several protease inhibitors have been identified, and some candidates are undergoing trials that may well prove to be effective antivirals against SARS-CoV-2.

Shaping axial identity during human pluripotent stem cell differentiation to neural crest cells

The neural crest (NC) is a multipotent cell population which can give rise to a vast array of derivatives including neurons and glia of the peripheral nervous system, cartilage, cardiac smooth muscle, melanocytes and sympathoadrenal cells. An attractive strategy to model human NC development and associated birth defects as well as produce clinically relevant cell populations for regenerative medicine applications involves the in vitro generation of NC from human pluripotent stem cells (hPSCs). However, in vivo, the potential of NC cells to generate distinct cell types is determined by their position along the anteroposterior (A–P) axis and, therefore the axial identity of hPSC-derived NC cells is an important aspect to consider. Recent advances in understanding the developmental origins of NC and the signalling pathways involved in its specification have aided the in vitro generation of human NC cells which are representative of various A–P positions. Here, we explore recent advances in methodologies of in vitro NC specification and axis patterning using hPSCs.

Role of macronutrient intake in the epigenetics of obesity

Obesity is caused by a combination of hereditary and environmental factors. Despite extensive study, contemporary through diet, exercise, education, surgery, and pharmacological treatments, no effective long-term solution has been found to this epidemic. Over the last decade, there has been a tremendous advancement in understanding the science of epigenetics, as well as a rise in public interest in learning more about the influence of diet and lifestyle choices on the health of an individual. Without affecting the underlying DNA sequence, epigenetic alterations impact gene expression. Previous animal studies have shown a link between the type of diet and expression or suppression of obesity genes, but there are very few human studies that demonstrate the relationship between dietary intake and obesity gene expression. This review highlights the effects of carbohydrates, lipids, and protein intake from the diet on obesity-related genes.

Tyrosine-O-sulfation is a widespread affinity enhancer among thrombin interactors

Tyrosine-O-sulfation is a common post-translational modification (PTM) of proteins following the cellular secretory pathway. First described in human fibrinogen, tyrosine-O-sulfation has long been associated with the modulation of protein–protein interactions in several physiological processes. A number of relevant interactions for hemostasis are largely dictated by this PTM, many of which involving the serine proteinase thrombin (FIIa), a central player in the blood-clotting cascade. Tyrosine sulfation is not limited to endogenous FIIa ligands and has also been found in hirudin, a well-known and potent thrombin inhibitor from the medicinal leech, Hirudo medicinalis. The discovery of hirudin led to successful clinical application of analogs of leech-inspired molecules, but also unveiled several other natural thrombin-directed anticoagulant molecules, many of which undergo tyrosine-O-sulfation. The presence of this PTM has been shown to enhance the anticoagulant properties of these peptides from a range of blood-feeding organisms, including ticks, mosquitos and flies. Interestingly, some of these molecules display mechanisms of action that mimic those of thrombin's bona fide substrates.

Npt2a as a target for treating hyperphosphatemia

Hyperphosphatemia results from an imbalance in phosphate (Pi) homeostasis. In patients with and without reduced kidney function, hyperphosphatemia is associated with cardiovascular complications. The current mainstays in the management of hyperphosphatemia are oral Pi binder and dietary Pi restriction. Although these options are employed in patients with chronic kidney disease (CKD), they seem inadequate to correct elevated plasma Pi levels. In addition, a paradoxical increase in expression of intestinal Pi transporter and uptake may occur. Recently, studies in rodents targeting the renal Na+/Pi cotransporter 2a (Npt2a), responsible for ∼70% of Pi reabsorption, have been proposed as a potential treatment option. Two compounds (PF-06869206 and BAY-767) have been developed which are selective for Npt2a. These Npt2a inhibitors significantly increased urinary Pi excretion consequently lowering plasma Pi and PTH levels. Additionally, increases in urinary excretions of Na+, Cl− and Ca2+ have been observed. Some of these results are also seen in models of reduced kidney function. Responses of FGF23, a phosphaturic hormone that has been linked to the development of left ventricular hypertrophy in CKD, are ambiguous. In this review, we discuss the recent advances on the role of Npt2a inhibition on Pi homeostasis as well as other pleiotropic effects observed with Npt2a inhibition.

The molecular pathogenesis of repeat expansion diseases

Expanded short tandem repeats in the genome cause various monogenic diseases, particularly neurological disorders. Since the discovery of a CGG repeat expansion in the FMR1 gene in 1991, more than 40 repeat expansion diseases have been identified to date. In the coding repeat expansion diseases, in which the expanded repeat sequence is located in the coding regions of genes, the toxicity of repeat polypeptides, particularly misfolding and aggregation of proteins containing an expanded polyglutamine tract, have been the focus of investigation. On the other hand, in the non-coding repeat expansion diseases, in which the expanded repeat sequence is located in introns or untranslated regions, the toxicity of repeat RNAs has been the focus of investigation. Recently, these repeat RNAs were demonstrated to be translated into repeat polypeptides by the novel mechanism of repeat-associated non-AUG translation, which has extended the research direction of the pathological mechanisms of this disease entity to include polypeptide toxicity. Thus, a common pathogenesis has been suggested for both coding and non-coding repeat expansion diseases. In this review, we briefly outline the major pathogenic mechanisms of repeat expansion diseases, including a loss-of-function mechanism caused by repeat expansion, repeat RNA toxicity caused by RNA foci formation and protein sequestration, and toxicity by repeat polypeptides. We also discuss perturbation of the physiological liquid-liquid phase separation state caused by these repeat RNAs and repeat polypeptides, as well as potential therapeutic approaches against repeat expansion diseases.

Exploring the multifunctionality of SR proteins

Members of the arginine–serine-rich protein family (SR proteins) are multifunctional RNA-binding proteins that have emerged as key determinants for mRNP formation, identity and fate. They bind to pre-mRNAs early during transcription in the nucleus and accompany bound transcripts until they are translated or degraded in the cytoplasm. SR proteins are mostly known for their essential roles in constitutive splicing and as regulators of alternative splicing. However, many additional activities of individual SR proteins, beyond splicing, have been reported in recent years. We will summarize the different functions of SR proteins and discuss how multifunctionality can be achieved. We will also highlight the difficulties of studying highly versatile SR proteins and propose approaches to disentangle their activities, which is transferrable to other multifunctional RBPs.

Regulatory long non-coding RNAs in root growth and development

As sessile organisms, plants have evolved sophisticated mechanisms of gene regulation to cope with changing environments. Among them, long non-coding RNAs (lncRNAs) are a class of RNAs regulating gene expression at both transcriptional and post-transcriptional levels. They are highly responsive to environmental cues or developmental processes and are generally involved in fine-tuning plant responses to these signals. Roots, in addition to anchoring the plant to the soil, allow it to absorb the major part of its mineral nutrients and water. Furthermore, roots directly sense environmental constraints such as mineral nutrient availability and abiotic or biotic stresses and dynamically adapt their growth and architecture. Here, we review the role of lncRNAs in the control of root growth and development. In particular, we highlight their action in fine-tuning primary root growth and the development of root lateral organs, such as lateral roots and symbiotic nodules. Lastly, we report their involvement in plant response to stresses and the regulation of nutrient assimilation and homeostasis, two processes leading to the modification of root architecture. LncRNAs could become interesting targets in plant breeding programs to subtly acclimate crops to coming environmental changes.