Showing papers in "Open Biology in 2019"
TL;DR: Factors that influence the temporal development of the infant microbiome are described, including the mode of delivery and gestational age at birth, maternal and infant perinatal antibiotic infusions, and feeding method—breastfeeding versus formula feeding.
Abstract: The majority of organisms that inhabit the human body reside in the gut. Since babies are born with an immature immune system, they depend on a highly synchronized microbial colonization process to ensure the correct microbes are present for optimal immune function and development. In a balanced microbiome, symbiotic and commensal species outcompete pathogens for resources. They also provide a protective barrier against chemical signals and toxic metabolites. In this targeted review we will describe factors that influence the temporal development of the infant microbiome, including the mode of delivery and gestational age at birth, maternal and infant perinatal antibiotic infusions, and feeding method-breastfeeding versus formula feeding. We will close by discussing wider environmental pressures and early intimate contact, particularly between mother and child, as they play a pivotal role in early microbial acquisition and community succession in the infant.
161 citations
TL;DR: Although the basic mechanisms of mRNA decay and translation are evolutionarily conserved, there are also unique aspects, such as the existence of six cap-binding translation initiation factor homologues, a novel decapping enzyme and an mRNA stabilizing complex that is recruited by RNA-binding proteins.
Abstract: In trypanosomes, RNA polymerase II transcription is polycistronic and individual mRNAs are excised by trans-splicing and polyadenylation. The lack of individual gene transcription control is compensated by control of mRNA processing, translation and degradation. Although the basic mechanisms of mRNA decay and translation are evolutionarily conserved, there are also unique aspects, such as the existence of six cap-binding translation initiation factor homologues, a novel decapping enzyme and an mRNA stabilizing complex that is recruited by RNA-binding proteins. High-throughput analyses have identified nearly a hundred regulatory mRNA-binding proteins, making trypanosomes valuable as a model system to investigate post-transcriptional regulation.
145 citations
TL;DR: This review considers how the ECM regulates cell shape, proliferation, differentiation and migration, and more recent work highlighting a key role of ECM in the morphogenesis of neural tissues.
Abstract: During development, both cells and tissues must acquire the correct shape to allow their proper function. This is especially relevant in the nervous system, where the shape of individual cell processes, such as the axons and dendrites, and the shape of entire tissues, such as the folding of the neocortex, are highly specialized. While many aspects of neural development have been uncovered, there are still several open questions concerning the mechanisms governing cell and tissue shape. In this review, we discuss the role of the extracellular matrix (ECM) in these processes. In particular, we consider how the ECM regulates cell shape, proliferation, differentiation and migration, and more recent work highlighting a key role of ECM in the morphogenesis of neural tissues.
135 citations
TL;DR: Several hypothetical models are presented based primarily on studies in model systems, which may or may not reflect the major lignification process in forest trees.
Abstract: Lignin is a major component of secondarily thickened plant cell walls and is considered to be the second most abundant biopolymer on the planet. At one point believed to be the product of a highly controlled polymerization procedure involving just three potential monomeric components (monolignols), it is becoming increasingly clear that the composition of lignin is quite flexible. Furthermore, the biosynthetic pathways to the major monolignols also appear to exhibit flexibility, particularly as regards the early reactions leading to the formation of caffeic acid from coumaric acid. The operation of parallel pathways to caffeic acid occurring at the level of shikimate esters or free acids may help provide robustness to the pathway under different physiological conditions. Several features of the pathway also appear to link monolignol biosynthesis to both generation and detoxification of hydrogen peroxide, one of the oxidants responsible for creating monolignol radicals for polymerization in the apoplast. Monolignol transport to the apoplast is not well understood. It may involve passive diffusion, although this may be targeted to sites of lignin initiation/polymerization by ordered complexes of both biosynthetic enzymes on the cytosolic side of the plasma membrane and structural anchoring of proteins for monolignol oxidation and polymerization on the apoplastic side. We present several hypothetical models to illustrate these ideas and stimulate further research. These are based primarily on studies in model systems, which may or may not reflect the major lignification process in forest trees.
113 citations
TL;DR: The molecular mechanisms and cellular implications of non-lysine ubiquitination are discussed, and open questions are outlined by outlining open questions and future perspectives in the field.
Abstract: Protein ubiquitination is of great cellular importance through its central role in processes such as degradation, DNA repair, endocytosis and inflammation. Canonical ubiquitination takes place on lysine residues, but in the past 15 years non-lysine ubiquitination on serine, threonine and cysteine has been firmly established. With the emerging importance of non-lysine ubiquitination, it is crucial to identify the responsible molecular machinery and understand the mechanistic basis for non-lysine ubiquitination. Here, we first provide an overview of the literature that has documented non-lysine ubiquitination. Informed by these examples, we then discuss the molecular mechanisms and cellular implications of non-lysine ubiquitination, and conclude by outlining open questions and future perspectives in the field.
98 citations
TL;DR: Accumulated experimental and clinical evidence has broadened the understanding of the seemingly paradoxical role of IL-17 in viral infections and suggests that IL- 17-targeted immunotherapy may be a promising therapeutic option.
Abstract: Viral infections cause substantial human morbidity and mortality, and are a significant health burden worldwide. Following a viral infection, the host may initiate complex antiviral immune responses to antagonize viral invasion and replication. However, proinflammatory antiviral immune responses pose a great threat to the host if not properly held in check. Interleukin (IL)-17 is a pleiotropic cytokine participating in a variety of physiological and pathophysiological conditions, including tissue integrity maintenance, cancer progression, autoimmune disease development and, more intriguingly, infectious diseases. Abundant evidence suggests that while IL-17 plays a crucial role in enhancing effective antiviral immune responses, it may also promote and exacerbate virus-induced illnesses. Accumulated experimental and clinical evidence has broadened our understanding of the seemingly paradoxical role of IL-17 in viral infections and suggests that IL-17-targeted immunotherapy may be a promising therapeutic option. Herein, we summarize current knowledge regarding the protective and pathogenic roles of IL-17 in viral infections, with emphasis on underlying mechanisms. The various and critical roles of IL-17 in viral infections necessitate the development of therapeutic strategies that are uniquely tailored to both the infectious agent and the infection environment.
96 citations
TL;DR: This review addresses the issue of the role of RNA–protein interactions in generating eukaryotic complexity, focusing on the newly characterized disordered RNA-binding motifs, moonlighting of metabolic enzymes, RNA- binding proteins interactions with different RNA species and their participation in regulatory networks of higher order.
Abstract: RNA–protein interactions are crucial for most biological processes in all organisms. However, it appears that the complexity of RNA-based regulation increases with the complexity of the organism, c...
94 citations
TL;DR: The progress in miRNA-related research, including study of its oncogene or tumour-suppressor roles and the advantages of miRNA biomarkers for CRC diagnosis, treatment and recurrence prediction are summarized.
Abstract: MicroRNAs (miRNAs) are one abundant class of small, endogenous non-coding RNAs, which regulate various biological processes by inhibiting expression of target genes. miRNAs have important functiona...
83 citations
TL;DR: The current understanding of how hunger is sensed, encoded and translated into foraging and feeding behaviours in the fruit fly is reviewed.
Abstract: Hunger is a motivational state that drives eating and food-seeking behaviour. In a psychological sense, hunger sets the goal that guides an animal in the pursuit of food. The biological basis underlying this purposive, goal-directed nature of hunger has been under intense investigation. With its rich behavioural repertoire and genetically tractable nervous system, the fruit fly Drosophila melanogaster has emerged as an excellent model system for studying the neural basis of hunger and hunger-driven behaviour. Here, we review our current understanding of how hunger is sensed, encoded and translated into foraging and feeding behaviours in the fruit fly.
82 citations
TL;DR: Genetic studies of the role of AMPK in mouse cancer suggest that, before disease arises, AMPK acts as a tumour suppressor that protects against cancer, with this protection being further enhanced by AMPK activators such as the biguanide phenformin.
Abstract: The AMP-activated protein kinase (AMPK) acts as a cellular energy sensor. Once switched on by increases in cellular AMP : ATP ratios, it acts to restore energy homeostasis by switching on catabolic pathways while switching off cell growth and proliferation. The canonical AMP-dependent mechanism of activation requires the upstream kinase LKB1, which was identified genetically to be a tumour suppressor. AMPK can also be switched on by increases in intracellular Ca2+, by glucose starvation and by DNA damage via non-canonical, AMP-independent pathways. Genetic studies of the role of AMPK in mouse cancer suggest that, before disease arises, AMPK acts as a tumour suppressor that protects against cancer, with this protection being further enhanced by AMPK activators such as the biguanide phenformin. However, once cancer has occurred, AMPK switches to being a tumour promoter instead, enhancing cancer cell survival by protecting against metabolic, oxidative and genotoxic stresses. Studies of genetic changes in human cancer also suggest diverging roles for genes encoding subunit isoforms, with some being frequently amplified, while others are mutated.
79 citations
TL;DR: It is shown that α-synuclein mutations that predispose to early-onset Parkinson's disease bestow an increased intrinsic sensitivity of α- synuclein to in vitro oxidation, which inspires a vision of predictive diagnostic, prognostic, prevention and treatment of degenerative diseases.
Abstract: Ageing is considered as a snowballing phenotype of the accumulation of damaged dysfunctional or toxic proteins and silent mutations (polymorphisms) that sensitize relevant proteins to oxidative damage as inborn predispositions to age-related diseases. Ageing is not a disease, but it causes (or shares common cause with) age-related diseases as suggested by similar slopes of age-related increase in the incidence of diseases and death. Studies of robust and more standard species revealed that dysfunctional oxidatively damaged proteins are the root cause of radiation-induced morbidity and mortality. Oxidized proteins accumulate with age and cause reversible ageing-like phenotypes with some irreversible consequences (e.g. mutations). Here, we observe in yeast that aggregation rate of damaged proteins follows the Gompertz law of mortality and review arguments for a causal relationship between oxidative protein damage, ageing and disease. Aerobes evolved proteomes remarkably resistant to oxidative damage, but imperfectly folded proteins become sensitive to oxidation. We show that α-synuclein mutations that predispose to early-onset Parkinson's disease bestow an increased intrinsic sensitivity of α-synuclein to in vitro oxidation. Considering how initially silent protein polymorphism becomes phenotypic while causing age-related diseases and how protein damage leads to genome alterations inspires a vision of predictive diagnostic, prognostic, prevention and treatment of degenerative diseases.
TL;DR: While germline control of transposons by the piRNA pathway is conserved, many pi RNA pathway genes are evolving rapidly under positive selection, and the pi RNA biogenesis machinery shows remarkable phylogenetic diversity.
Abstract: Transposons are major genome constituents that can mobilize and trigger mutations, DNA breaks and chromosome rearrangements. Transposon silencing is particularly important in the germline, which is dedicated to transmission of the inherited genome. Piwi-interacting RNAs (piRNAs) guide a host defence system that transcriptionally and post-transcriptionally silences transposons during germline development. While germline control of transposons by the piRNA pathway is conserved, many piRNA pathway genes are evolving rapidly under positive selection, and the piRNA biogenesis machinery shows remarkable phylogenetic diversity. Conservation of core function combined with rapid gene evolution is characteristic of a host-pathogen arms race, suggesting that transposons and the piRNA pathway are engaged in an evolutionary tug of war that is driving divergence of the biogenesis machinery. Recent studies suggest that this process may produce biochemical incompatibilities that contribute to reproductive isolation and species divergence.
TL;DR: The recent findings in the field of ADPr are summarized, which support the impact of this modification in human pathophysiology and highlight the curative potential of targeting ADPr for translational and molecular medicine.
Abstract: ADP-ribosylation (ADPr) is a reversible post-translational modification of proteins, which controls major cellular and biological processes, including DNA damage repair, cell proliferation and diff...
TL;DR: In this review, foundational knowledge in mitochondrial biology is discussed and snapshots of recent advances that showcase how mitochondrial function regulates other cellular responses are provided.
Abstract: Mitochondria are iconic structures in biochemistry and cell biology, traditionally referred to as the powerhouse of the cell due to a central role in energy production. However, modern-day mitochondria are recognized as key players in eukaryotic cell biology and are known to regulate crucial cellular processes, including calcium signalling, cell metabolism and cell death, to name a few. In this review, we will discuss foundational knowledge in mitochondrial biology and provide snapshots of recent advances that showcase how mitochondrial function regulates other cellular responses.
TL;DR: This work defines characterized and uncharacterized proteins for human, budding yeast and fission yeast, and identifies a set of conserved but unstudied proteins in S. pombe, and classify them based on a combination of orthogonal attributes determined by large-scale experimental and comparative methods.
Abstract: The first decade of genome sequencing stimulated an explosion in the characterization of unknown proteins. More recently, the pace of functional discovery has slowed, leaving around 20% of the proteins even in well-studied model organisms without informative descriptions of their biological roles. Remarkably, many uncharacterized proteins are conserved from yeasts to human, suggesting that they contribute to fundamental biological processes (BP). To fully understand biological systems in health and disease, we need to account for every part of the system. Unstudied proteins thus represent a collective blind spot that limits the progress of both basic and applied biosciences. We use a simple yet powerful metric based on Gene Ontology BP terms to define characterized and uncharacterized proteins for human, budding yeast and fission yeast. We then identify a set of conserved but unstudied proteins in S. pombe, and classify them based on a combination of orthogonal attributes determined by large-scale experimental and comparative methods. Finally, we explore possible reasons why these proteins remain neglected, and propose courses of action to raise their profile and thereby reap the benefits of completing the catalogue of proteins’ biological roles.
TL;DR: A consensus set of 117 genes enriched in DNA replication, DNA repair and cell cycle regulators that promote survival when ATR kinase activity is suppressed is delineated, finding that the loss of the POLE3/POLE4 proteins, which are DNA polymerase ε accessory subunits, results in marked hypersensitivity to ATR inhibition.
Abstract: The response to DNA replication stress in eukaryotes is under the control of the ataxia-telangiectasia and Rad3-related (ATR) kinase. ATR responds to single-stranded (ss) DNA to stabilize distressed DNA replication forks, modulate DNA replication firing and prevent cells with damaged DNA or incomplete DNA replication from entering into mitosis. Furthermore, inhibitors of ATR are currently in clinical development either as monotherapies or in combination with agents that perturb DNA replication. To gain a genetic view of the cellular pathways requiring ATR kinase function, we mapped genes whose mutation causes hypersensitivity to ATR inhibitors with genome-scale CRISPR/Cas9 screens. We delineate a consensus set of 117 genes enriched in DNA replication, DNA repair and cell cycle regulators that promote survival when ATR kinase activity is suppressed. We validate 14 genes from this set and report genes not previously described to modulate response to ATR inhibitors. In particular we found that the loss of the POLE3/POLE4 proteins, which are DNA polymerase e accessory subunits, results in marked hypersensitivity to ATR inhibition. We anticipate that this 117-gene set will be useful for the identification of genes involved in the regulation of genome integrity and the characterization of new biological processes involving ATR, and may reveal biomarkers of ATR inhibitor response in the clinic.
TL;DR: Recent progress in generating Alzheimer's, Parkinson's and Huntington's disease models from patient-derived iPSCs are reviewed and novel discoveries of pathological mechanisms and drug evaluations that have used these patient iPSC-derived neuronal models are described.
Abstract: Adult-onset neurodegenerative diseases are among the most difficult human health conditions to model for drug development. Most genetic or toxin-induced cell and animal models cannot faithfully rec...
TL;DR: This review focuses on the functions of JNK in Drosophila imaginal discs, where it has been reported that it can induce both cell death and cell proliferation, and proposes that the pro-apoptotic and theProliferative functions are intrinsic properties of J NK activity.
Abstract: The Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase family. It appears to be conserved in all animal species where it regulates important physiological functions involved in apoptosis, cell migration, cell proliferation and regeneration. In this review, we focus on the functions of JNK in Drosophila imaginal discs, where it has been reported that it can induce both cell death and cell proliferation. We discuss this apparent paradox in the light of recent findings and propose that the pro-apoptotic and the pro-proliferative functions are intrinsic properties of JNK activity. Whether one function or another is predominant depends on the cellular context.
TL;DR: The recent strategies applied to metabolic engineering of S. cerevisiae for the production of fatty acid-derived biofuels and for improvement of the titre, rate and yield (TRY) are reviewed.
Abstract: The yeast Saccharomyces cerevisiae is a widely used cell factory for the production of fuels and chemicals, in particular ethanol, a biofuel produced in large quantities. With a need for high-energy-density fuels for jets and heavy trucks, there is, however, much interest in the biobased production of hydrocarbons that can be derived from fatty acids. Fatty acids also serve as precursors to a number of oleochemicals and hence provide interesting platform chemicals. Here, we review the recent strategies applied to metabolic engineering of S. cerevisiae for the production of fatty acid-derived biofuels and for improvement of the titre, rate and yield (TRY). This includes, for instance, redirection of the flux towards fatty acids through engineering of the central carbon metabolism, balancing the redox power and varying the chain length of fatty acids by enzyme engineering. We also discuss the challenges that currently hinder further TRY improvements and the potential solutions in order to meet the requirements for commercial application.
TL;DR: Three widely accepted ideas that underpin the current study of the evolution of photosynthesis are reviewed and it is demonstrated that these three ideas are often grounded in incorrect assumptions built on more assumptions with no experimental or observational support.
Abstract: Sam Granick opened his seminal 1957 paper titled 'Speculations on the origins and evolution of photosynthesis' with the assertion that there is a constant urge in human beings to seek beginnings (I concur). This urge has led to an incessant stream of speculative ideas and debates on the evolution of photosynthesis that started in the first half of the twentieth century and shows no signs of abating. Some of these speculative ideas have become commonplace, are taken as fact, but find little support. Here, I review and scrutinize three widely accepted ideas that underpin the current study of the evolution of photosynthesis: first, that the photochemical reaction centres used in anoxygenic photosynthesis are more primitive than those in oxygenic photosynthesis; second, that the probability of acquiring photosynthesis via horizontal gene transfer is greater than the probability of losing photosynthesis; and third, and most important, that the origin of anoxygenic photosynthesis pre-dates the origin of oxygenic photosynthesis. I shall attempt to demonstrate that these three ideas are often grounded in incorrect assumptions built on more assumptions with no experimental or observational support. I hope that this brief review will not only serve as a cautionary tale but also that it will open new avenues of research aimed at disentangling the complex evolution of photosynthesis and its impact on the early history of life and the planet.
TL;DR: Gaining mechanistic insights into axon death signalling broadens the understanding beyond a simple injury model, and harbours the potential to define targets for therapeutic intervention in a broad range of human axonopathies.
Abstract: Axon loss is a shared feature of nervous systems being challenged in neurological disease, by chemotherapy or mechanical force. Axons take up the vast majority of the neuronal volume, thus numerous axonal intrinsic and glial extrinsic support mechanisms have evolved to promote lifelong axonal survival. Impaired support leads to axon degeneration, yet underlying intrinsic signalling cascades actively promoting the disassembly of axons remain poorly understood in any context, making the development to attenuate axon degeneration challenging. Wallerian degeneration serves as a simple model to study how axons undergo injury-induced axon degeneration (axon death). Severed axons actively execute their own destruction through an evolutionarily conserved axon death signalling cascade. This pathway is also activated in the absence of injury in diseased and challenged nervous systems. Gaining insights into mechanisms underlying axon death signalling could therefore help to define targets to block axon loss. Herein, we summarize features of axon death at the molecular and subcellular level. Recently identified and characterized mediators of axon death signalling are comprehensively discussed in detail, and commonalities and differences across species highlighted. We conclude with a summary of engaged axon death signalling in humans and animal models of neurological conditions. Thus, gaining mechanistic insights into axon death signalling broadens our understanding beyond a simple injury model. It harbours the potential to define targets for therapeutic intervention in a broad range of human axonopathies.
TL;DR: The post-translational modifications that impact upon hnRNPK function on gene expression programmes and different disease states are described and knowledge is key in allowing us to better understand the mechanism of hn RNPK regulation.
Abstract: Heterogeneous nuclear ribonucleoprotein K (hnRNPK), a ubiquitously occurring RNA-binding protein (RBP), can interact with numerous nucleic acids and various proteins and is involved in a number of cellular functions including transcription, translation, splicing, chromatin remodelling, etc. Through its abundant biological functions, hnRNPK has been implicated in cellular events including proliferation, differentiation, apoptosis, DNA damage repair and the stress and immune responses. Thus, it is critical to understand the mechanism of hnRNPK regulation and its downstream effects on cancer and other diseases. A number of recent studies have highlighted that several post-translational modifications (PTMs) possibly play an important role in modulating hnRNPK function. Phosphorylation is the most widely occurring PTM in hnRNPK. For example, in vivo analyses of sites such as S116 and S284 illustrate the purpose of PTM of hnRNPK in altering its subcellular localization and its ability to bind target nucleic acids or proteins. Other PTMs such as methylation, ubiquitination, sumoylation, glycosylation and proteolytic cleavage are increasingly implicated in the regulation of DNA repair, cellular stresses and tumour growth. In this review, we describe the PTMs that impact upon hnRNPK function on gene expression programmes and different disease states. This knowledge is key in allowing us to better understand the mechanism of hnRNPK regulation.
TL;DR: What is known about iRhom molecular mechanisms and relevance in known pathologies is discussed, and it seems likely that as the involvement of iRhoms in human diseases is increasingly recognized, they will become the focus of pharmaceutical interest.
Abstract: iRhom proteins are catalytically inactive relatives of rhomboid intramembrane proteases. There is a rapidly growing body of evidence that these pseudoenzymes have a central function in regulating inflammatory and growth factor signalling and consequent roles in many diseases. iRhom pseudoproteases have evolved new domains from their proteolytic ancestors, which are integral to their modular regulation and functions. Although we cannot yet conclude the full extent of their molecular and cellular mechanisms, there is a clearly emerging theme that they regulate the stability and trafficking of other membrane proteins. In the best understood case, iRhoms act as regulatory cofactors of the ADAM17 protease, controlling its function of shedding cytokines and growth factors. It seems likely that as the involvement of iRhoms in human diseases is increasingly recognized, they will become the focus of pharmaceutical interest, and here we discuss what is known about their molecular mechanisms and relevance in known pathologies.
TL;DR: Current knowledge of tissue tropism in Trypanosoma infections in mammals is discussed, potential mechanisms of tissue entry are described, relevant findings from other parasitology fields are discussed, and new questions raised by recent discoveries are reflected.
Abstract: Parasitic diseases, such as sleeping sickness, Chagas disease and malaria, remain a major cause of morbidity and mortality worldwide, but particularly in tropical, developing countries. Controlling these diseases requires a better understanding of host-parasite interactions, including a deep appreciation of parasite distribution in the host. The preferred accumulation of parasites in some tissues of the host has been known for many years, but recent technical advances have allowed a more systematic analysis and quantifications of such tissue tropisms. The functional consequences of tissue tropism remain poorly studied, although it has been associated with important aspects of disease, including transmission enhancement, treatment failure, relapse and clinical outcome. Here, we discuss current knowledge of tissue tropism in Trypanosoma infections in mammals, describe potential mechanisms of tissue entry, comparatively discuss relevant findings from other parasitology fields where tissue tropism has been extensively investigated, and reflect on new questions raised by recent discoveries and their potential impact on clinical treatment and disease control strategies.
TL;DR: The role of cellular and systemic mechanisms of ageing and their role in ageing-associated diseases are discussed and may become therapeutic targets of therapies aimed at extending the healthy lifespan.
Abstract: Ageing appears to be a nearly universal feature of life, ranging from unicellular microorganisms to humans. Longevity depends on the maintenance of cellular functionality, and an organism's ability to respond to stress has been linked to functional maintenance and longevity. Stress response pathways might indeed become therapeutic targets of therapies aimed at extending the healthy lifespan. Various progeroid syndromes have been linked to genome instability, indicating an important causal role of DNA damage accumulation in the ageing process and the development of age-related pathologies. Recently, non-cell-autonomous mechanisms including the systemic consequences of cellular senescence have been implicated in regulating organismal ageing. We discuss here the role of cellular and systemic mechanisms of ageing and their role in ageing-associated diseases.
TL;DR: This review discusses studies conducted in the mouse models of five major monogenic causes of Intellectual disability and autism spectrum disorders that reveal that the effects of these mutations converge onto similar or related aetiological pathways, consequently giving rise to the typical phenotype of cognitive, social and emotional deficits that are characteristic of ID and ASDs.
Abstract: Normal brain development is highly dependent on the timely coordinated actions of genetic and environmental processes, and an aberration can lead to neurodevelopmental disorders (NDDs). Intellectual disability (ID) and autism spectrum disorders (ASDs) are a group of co-occurring NDDs that affect between 3% and 5% of the world population, thus presenting a great challenge to society. This problem calls for the need to understand the pathobiology of these disorders and to design new therapeutic strategies. One approach towards this has been the development of multiple analogous mouse models. This review discusses studies conducted in the mouse models of five major monogenic causes of ID and ASDs: Fmr1, Syngap1, Mecp2, Shank2/3 and Neuroligins/Neurnexins. These studies reveal that, despite having a diverse molecular origin, the effects of these mutations converge onto similar or related aetiological pathways, consequently giving rise to the typical phenotype of cognitive, social and emotional deficits that are characteristic of ID and ASDs. This convergence, therefore, highlights common pathological nodes that can be targeted for therapy. Other than conventional therapeutic strategies such as non-pharmacological corrective methods and symptomatic alleviation, multiple studies in mouse models have successfully proved the possibility of pharmacological and genetic therapy enabling functional recovery.
TL;DR: The skeletal vascular bed is complex, heterogeneous and characterized by distinct capillary subtypes (type H and type L), which exhibit differential expression of angiocrine factors, which differentially regulate osteogenesis and haematopoiesis, and drive disease states in the skeletal system.
Abstract: Skeletal vasculature plays a central role in the maintenance of microenvironments for osteogenesis and haematopoiesis. In addition to supplying oxygen and nutrients, vasculature provides a number of inductive factors termed as angiocrine signals. Blood vessels drive recruitment of osteoblast precursors and bone formation during development. Angiogenesis is indispensable for bone repair and regeneration. Dysregulation of the angiocrine crosstalk is a hallmark of ageing and pathobiological conditions in the skeletal system. The skeletal vascular bed is complex, heterogeneous and characterized by distinct capillary subtypes (type H and type L), which exhibit differential expression of angiocrine factors. Furthermore, distinct blood vessel subtypes with differential angiocrine profiles differentially regulate osteogenesis and haematopoiesis, and drive disease states in the skeletal system. This review provides an overview of the role of angiocrine signals in bone during homeostasis and disease.
TL;DR: The data show that Topoisomerase III beta is necessary to prevent the accumulation of excessive R-loops and identify TOP3B as a putative cancer gene, and support recent data showing that R-Loops are involved in cancer aetiology.
Abstract: Topoisomerase III beta (TOP3B) is one of the least understood members of the topoisomerase family of proteins and remains enigmatic. Our recent data shed light on the function and relevance of TOP3B to disease. A homozygous deletion for the TOP3B gene was identified in a patient with bilateral renal cancer. Analyses in both patient and modelled human cells show the disruption of TOP3B causes genome instability with a rise in DNA damage and chromosome bridging (mis-segregation). The primary molecular defect underlying this pathology is a significant increase in R-loop formation. Our data show that TOP3B is necessary to prevent the accumulation of excessive R-loops and identify TOP3B as a putative cancer gene, and support recent data showing that R-loops are involved in cancer aetiology.
TL;DR: A critical review of this burgeoning literature to make sense of what has been learned so far and highlight the experimental strategies that have been most useful in gleaning physiologically relevant information is provided.
Abstract: The evolutionarily conserved Notch signalling pathway regulates the differentiation and function of mature T lymphocytes with major context-dependent consequences in host defence, autoimmunity and alloimmunity. The emerging effects of Notch signalling in T cell responses build upon a more established role for Notch in T cell development. Here, we provide a critical review of this burgeoning literature to make sense of what has been learned so far and highlight the experimental strategies that have been most useful in gleaning physiologically relevant information. We outline the functional consequences of Notch signalling in mature T cells in addition to key specific Notch ligand-receptor interactions and downstream molecular signalling pathways. Our goal is to help clarify future directions for this expanding body of work and the best approaches to answer important open questions.
TL;DR: Data show that miR-149-3p can reverse CD8+ T-cell exhaustion and reveal it to be a potential antitumour immunotherapeutic agent in breast cancer.
Abstract: Blockade of inhibitory receptors (IRs) is one of the most effective immunotherapeutic approaches to treat cancer. Dysfunction of miRNAs is a major cause of aberrant expression of IRs and contributes to the immune escape of cancer cells. How miRNAs regulate immune checkpoint proteins in breast cancer remains largely unknown. In this study, downregulation of miRNAs was observed in PD-1-overexpressing CD8+ T cells using miRNA array analysis of mouse breast cancer homografts. The data reveal that miR-149-3p was predicted to bind the 3'UTRs of mRNAs encoding T-cell inhibitor receptors PD-1, TIM-3, BTLA and Foxp1. Treatment of CD8+ T cells with an miR-149-3p mimic reduced apoptosis, attenuated changes in mRNA markers of T-cell exhaustion and downregulated mRNAs encoding PD-1, TIM-3, BTLA and Foxp1. On the other hand, T-cell proliferation and secretion of effector cytokines indicative of increased T-cell activation (IL-2, TNF-α, IFN-γ) were upregulated after miR-149-3p mimic treatment. Moreover, the treatment with a miR-149-3p mimic promoted the capacity of CD8+ T cells to kill targeted 4T1 mouse breast tumour cells. Collectively, these data show that miR-149-3p can reverse CD8+ T-cell exhaustion and reveal it to be a potential antitumour immunotherapeutic agent in breast cancer.