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Artemisinin susceptibility in the malaria parasite Plasmodium falciparum: propellers, adaptor proteins and the need for cellular healing

2020-10-23T00:00

Studies of the susceptibility of Plasmodium falciparum to the artemisinin family of antimalarial drugs provide a complex picture of partial resistance (tolerance) associated with increased parasite survival in vitro and in vivo. We present an overview of the genetic loci that, in mutant form, can independently elicit parasite tolerance. These encode Kelch propeller domain protein PfK13, ubiquitin hydrolase UBP-1, actin filament-organising protein Coronin, also carrying a propeller domain, and the trafficking adaptor subunit AP-2μ. Detailed studies of these proteins and the functional basis of artemisinin tolerance in blood-stage parasites are enabling a new synthesis of our understanding to date. To guide further experimental work, we present two major conclusions. First, we propose a dual-component model of artemisinin tolerance in P. falciparum comprising suppression of artemisinin activation in early ring stage by reducing endocytic haemoglobin capture from host cytosol, coupled with enhancement of cellular healing mechanisms in surviving cells. Second, these two independent requirements limit the likelihood of development of complete artemisinin resistance by P. falciparum, favouring deployment of existing drugs in new schedules designed to exploit these biological limits, thus extending the useful life of current combination therapies.

This review summarises evidence that tolerance of the antimalarial drug artemisinin by Plasmodium falciparum requires suppression of endocytic capture of host erythrocyte haemoglobin, an activator of the drug in early-stage parasites, coupled with an enhanced capacity for repair of cellular damage.

The impact of the Fungus-Host-Microbiota interplay upon Candida albicans infections: current knowledge and new perspectives

2020-11-24T00:00

Candida albicans is a major fungal pathogen of humans. It exists as a commensal in the oral cavity, gut or genital tract of most individuals, constrained by the local microbiota, epithelial barriers and immune defences. Their perturbation can lead to fungal outgrowth and the development of mucosal infections such as oropharyngeal or vulvovaginal candidiasis, and patients with compromised immunity are susceptible to life-threatening systemic infections. The importance of the interplay between fungus, host and microbiota in driving the transition from C. albicans commensalism to pathogenicity is widely appreciated. However, the complexity of these interactions, and the significant impact of fungal, host and microbiota variability upon disease severity and outcome, are less well understood. Therefore, we summarise the features of the fungus that promote infection, and how genetic variation between clinical isolates influences pathogenicity. We discuss antifungal immunity, how this differs between mucosae, and how individual variation influences a person's susceptibility to infection. Also, we describe factors that influence the composition of gut, oral and vaginal microbiotas, and how these affect fungal colonisation and antifungal immunity. We argue that a detailed understanding of these variables, which underlie fungal-host-microbiota interactions, will present opportunities for directed antifungal therapies that benefit vulnerable patients.

The complexity and variability of FunHoMic interactions between the fungal pathogen, its human host and the Microbiota strongly influence the development and outcomes of the superficial and systemic Candida albicans infections that plague human health worldwide.

The PEP-pyruvate-oxaloacetate node: variation at the heart of metabolism

2020-12-08T00:00

At the junction between the glycolysis and the tricarboxylic acid cycle—as well as various other metabolic pathways—lies the phosphoenolpyruvate (PEP)-pyruvate-oxaloacetate node (PPO-node). These three metabolites form the core of a network involving at least eleven different types of enzymes, each with numerous subtypes. Obviously, no single organism maintains each of these eleven enzymes; instead, different organisms possess different subsets in their PPO-node, which results in a remarkable degree of variation, despite connecting such deeply conserved metabolic pathways as the glycolysis and the tricarboxylic acid cycle. The PPO-node enzymes play a crucial role in cellular energetics, with most of them involved in (de)phosphorylation of nucleotide phosphates, while those responsible for malate conversion are important redox enzymes. Variations in PPO-node therefore reflect the different energetic niches that organisms can occupy. In this review, we give an overview of the biochemistry of these eleven PPO-node enzymes. We attempt to highlight the variation that exists, both in PPO-node compositions, as well as in the roles that the enzymes can have within those different settings, through various recent discoveries in both bacteria and archaea that reveal deviations from canonical functions.

Three metabolites, phosphoenolpyruvate, pyruvate and oxaloacetate together form the PPO-node, and are interconnected by a subset of 11 different enzymes; the current knowledge regarding these enzymes at the heart of metabolism is presented.

Hairy cell leukemia and COVID-19 adaptation of treatment guidelines

2021-05-04T00:00

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.

Astrocytes and microglia in neurodegenerative diseases: Lessons from human in vitro models

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Astrocytes and microglia key fulfil homeostatic and immune functions in the CNS.

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Dysfunction of these cell types is implicated in neurodegenerative diseases.

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Understanding cellular autonomy and early pathogenic changes is a key goal.

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New human iPSC models will inform on disease mechanisms and therapy development.

Both astrocytes and microglia fulfil homeostatic and immune functions in the healthy CNS. Dysfunction of these cell types have been implicated in the pathomechanisms of several neurodegenerative diseases. Understanding the cellular autonomy and early pathological changes in these cell types may inform drug screening and therapy development. While animal models and post-mortem tissue have been invaluable in understanding disease processes, the advent of human in vitro models provides a unique insight into disease biology as a manipulable model system obtained directly from patients. Here, we discuss the different human in vitro models of astrocytes and microglia and outline the phenotypes that have been recapitulated in these systems.

Spatiotemporal regulation of hydrogen sulfide signaling in the kidney

2021-04-02T00:00

Hydrogen sulfide (H₂S) has long been recognized as a putrid, toxic gas. However, as a result of intensive biochemical research in the past two decades, H₂S is now considered to be the third gasotransmitter alongside nitric oxide (NO) and carbon monoxide (CO) in mammalian systems. H₂S-producing enzymes are expressed in all organs, playing an important role in their physiology. In the kidney, H₂S is a critical regulator of vascular and cellular function, although the mechanisms that affect (sub)cellular levels of H₂S are not precisely understood. H₂S modulates systemic and renal blood flow, glomerular filtration rate and the renin-angiotensin axis through direct inhibition of nitric oxide synthesis. Further, H₂S affects cellular function by modulating protein activity via post-translational protein modification: a process termed persulfidation. Persulfidation modulates protein activity, protein localization and protein-protein interactions. Additionally, acute kidney injury (AKI) due to mitochondrial dysfunction, which occurs during hypoxia or ischemia-reperfusion (IR), is attenuated by H₂S. H₂S enhances ATP production, prevents damage due to free radicals and regulates endoplasmic reticulum stress during IR. In this review, we discuss current insights in the (sub)cellular regulation of H₂S anabolism, retention and catabolism, with relevance to spatiotemporal regulation of renal H₂S levels. Together, H₂S is a versatile gasotransmitter with pleiotropic effects on renal function and offers protection against AKI. Unraveling the mechanisms that modulate (sub)cellular signaling of H₂S not only expands fundamental insight in the regulation of functional effects mediated by H₂S, but can also provide novel therapeutic targets to prevent kidney injury due to hypoxic or ischemic injury.

The central role of mitochondrial fitness on antiviral defenses: An advocacy for physical activity during the COVID-19 pandemic

2021-04-23T00:00

Mitochondria are central regulators of cellular metabolism, most known for their role in energy production. They can be “enhanced” by physical activity (including exercise), which increases their integrity, efficiency and dynamic adaptation to stressors, in short “mitochondrial fitness”. Mitochondrial fitness is closely associated with cardiorespiratory fitness and physical activity. Given the importance of mitochondria in immune functions, it is thus not surprising that cardiorespiratory fitness is also an integral determinant of the antiviral host defense and vulnerability to infection.

Here, we first briefly review the role of physical activity in viral infections. We then summarize mitochondrial functions that are relevant for the antiviral immune response with a particular focus on the current Coronavirus Disease (COVID-19) pandemic and on innate immune function. Finally, the modulation of mitochondrial and cardiorespiratory fitness by physical activity, aging and the chronic diseases that represent the most common comorbidities of COVID-19 is discussed.

We conclude that a high mitochondrial - and related cardiorespiratory - fitness should be considered as protective factors for viral infections, including COVID-19. This assumption is corroborated by reduced mitochondrial fitness in many established risk factors of COVID-19, like age, various chronic diseases or obesity. We argue for regular analysis of the cardiorespiratory fitness of COVID-19 patients and the promotion of physical activity – with all its associated health benefits – as preventive measures against viral infection.

Major COVID-19 risk factors are associated with reduced mitochondrial fitness.

SARS-coronavirus-2 infection is associated with various mitochondrial dysfunctions, also impairing the innate immune system.

Physical activity enhances immune functions, mitochondrial fitness and cardiorespiratory fitness.

Mitochondrial fitness may be an underlying molecular link between established risk factors for COVID-19.

Increasing mitochondrial and cardiorespiratory fitness, e.g. by appropriate physical activity, consequently may be a powerful preventive measure against viral infection, in particular by SARS-coronavirus-2.

Carbon/nitrogen homeostasis control in cyanobacteria

2019-10-16T00:00

Carbon/nitrogen (C/N) balance sensing is a key requirement for the maintenance of cellular homeostasis. Therefore, cyanobacteria have evolved a sophisticated signal transduction network targeting the metabolite 2-oxoglutarate (2-OG), the carbon skeleton for nitrogen assimilation. It serves as a status reporter for the cellular C/N balance that is sensed by transcription factors NtcA and NdhR and the versatile PII-signaling protein. The PII protein acts as a multitasking signal-integrating regulator, combining the 2-OG signal with the energy state of the cell through adenyl-nucleotide binding. Depending on these integrated signals, PII orchestrates metabolic activities in response to environmental changes through binding to various targets. In addition to 2-OG, other status reporter metabolites have recently been discovered, mainly indicating the carbon status of the cells. One of them is cAMP, which is sensed by the PII-like protein SbtB. The present review focuses, with a main emphasis on unicellular model strains Synechoccus elongatus and Synechocystis sp. PCC 6803, on the physiological framework of these complex regulatory loops, the tight linkage to metabolism and the molecular mechanisms governing the signaling processes.

This review presents the current knowledge on the sophisticated signal transduction network evolved in cyanobacteria to maintain carbon/nitrogen homeostasis.

Mechanistic insights into host adaptation, virulence and epidemiology of the phytopathogen Xanthomonas

2019-10-03T00:00

Xanthomonas is a well-studied genus of bacterial plant pathogens whose members cause a variety of diseases in economically important crops worldwide. Genomic and functional studies of these phytopathogens have provided significant understanding of microbial-host interactions, bacterial virulence and host adaptation mechanisms including microbial ecology and epidemiology. In addition, several strains of Xanthomonas are important as producers of the extracellular polysaccharide, xanthan, used in the food and pharmaceutical industries. This polymer has also been implicated in several phases of the bacterial disease cycle. In this review, we summarise the current knowledge on the infection strategies and regulatory networks controlling virulence and adaptation mechanisms from Xanthomonas species and discuss the novel opportunities that this body of work has provided for disease control and plant health.

Here, we discuss the current knowledge surrounding regulatory networks and systems that control virulence and adaption mechanisms in Xanthomonas species. Additionally, we detail how study of these pathogens has provided novel opportunities for disease control and plant health.

Heart failure—emerging roles for the mitochondrial pyruvate carrier

2021-01-20T00:00

The mitochondrial pyruvate carrier (MPC) is the entry point for the glycolytic end-product pyruvate to the mitochondria. MPC activity, which is controlled by its abundance and post-translational regulation, determines whether pyruvate is oxidised in the mitochondria or metabolised in the cytosol. MPC serves as a crucial metabolic branch point that determines the fate of pyruvate in the cell, enabling metabolic adaptations during health, such as exercise, or as a result of disease. Decreased MPC expression in several cancers limits the mitochondrial oxidation of pyruvate and contributes to lactate accumulation in the cytosol, highlighting its role as a contributing, causal mediator of the Warburg effect. Pyruvate is handled similarly in the failing heart where a large proportion of it is reduced to lactate in the cytosol instead of being fully oxidised in the mitochondria. Several recent studies have found that the MPC abundance was also reduced in failing human and mouse hearts that were characterised by maladaptive hypertrophic growth, emulating the anabolic scenario observed in some cancer cells. In this review we discuss the evidence implicating the MPC as an important, perhaps causal, mediator of heart failure progression.

Beyond DNA repair and chromosome instability—Fanconi anaemia as a cellular senescence-associated syndrome

2021-03-15T00:00

Fanconi anaemia (FA) is the most frequent inherited bone marrow failure syndrome, due to mutations in genes encoding proteins involved in replication fork protection, DNA interstrand crosslink repair and replication rescue through inducing double-strand break repair and homologous recombination. Clinically, FA is characterised by aplastic anaemia, congenital defects and cancer predisposition. In in vitro studies, FA cells presented hallmarks defining senescent cells, including p53-p21 axis activation, altered telomere length, mitochondrial dysfunction, chromatin alterations, and a pro-inflammatory status. Senescence is a programme leading to proliferation arrest that is involved in different physiological contexts, such as embryogenesis, tissue remodelling and repair and guarantees tumour suppression activity. However, senescence can become a driving force for developmental abnormalities, aging and cancer. Herein, we summarise the current knowledge in the field to highlight the mutual relationships between FA and senescence that lead us to consider FA not only as a DNA repair and chromosome fragility syndrome but also as a “senescence syndrome”.

Molecular biology of Hodgkin lymphoma

2021-03-08T00:00

Classical Hodgkin lymphoma (cHL) is unique among lymphoid malignancies in several key biological features. (i) The Hodgkin and Reed-Sternberg (HRS) tumor cells are rare among an extensive and complex microenvironment. (ii) They derive from B cells, but have largely lost the B-cell typical gene expression program. (iii) Their specific origin appears to be pre-apoptotic germinal center (GC) B cells. (iv) They consistently develop bi- or multinucleated Reed-Sternberg cells from mononuclear Hodgkin cells. (v) They show constitutive activation of numerous signaling pathways. Recent studies have begun to uncover the basis of these specific features of cHL: HRS cells actively orchestrate their complex microenvironment and attract many distinct subsets of immune cells into the affected tissues, to support their survival and proliferation, and to create an immunosuppressive environment. Reed-Sternberg cells are generated by incomplete cytokinesis and refusion of Hodgkin cells. Epstein-Barr virus (EBV) plays a major role in the rescue of crippled GC B cells from apoptosis and hence is a main player in early steps of lymphomagenesis of EBV⁺ cHL cases. The analysis of the landscape of genetic lesions in HRS cells so far did not reveal any highly recurrent HRS cell-specific lesions, but major roles of genetic lesions in members of the NF-κB and JAK/STAT pathways and of factors of immune evasion. It is perhaps the combination of the genetic lesions and the peculiar cellular origin of HRS cells that are disease defining. A combination of such genetic lesions and multiple cellular interactions with cells in the microenvironment causes the constitutive activation of many signaling pathways, often interacting in complex fashions. In nodular lymphocyte predominant Hodgkin lymphoma, the GC B cell-derived tumor cells have largely retained their typical GC B-cell expression program and follicular microenvironment. For IgD-positive cases, bacterial antigen triggering has recently been implicated in early stages of its pathogenesis.

HIGH RESOLUTION MASS SPECTROMETRY IN LIPIDOMICS

2020-03-31T00:00

The boost of research output in lipidomics during the last decade is tightly linked to improved instrumentation in mass spectrometry. Associated with this trend is the shift from low resolution—toward high‐resolution lipidomics platforms. This review article summarizes the state of the art in the lipidomics field with a particular focus on the merits of high mass resolution. Following some theoretical considerations on the benefits of high mass resolution in lipidomics, it starts with a historical perspective on lipid analysis by sector instruments and moves further to today's instrumental approaches, including shotgun lipidomics, liquid chromatography–mass spectrometry, matrix‐assisted laser desorption ionization‐time‐of‐flight, and imaging lipidomics. Subsequently, several data processing and data analysis software packages are critically evaluated with all their pros and cons. Finally, this article emphasizes the importance and necessity of quality standards as the field evolves from its pioneering phase into a mature and robust omics technology and lists various initiatives for improving the applicability of lipidomics. © 2020 The Authors. Mass Spectrometry Reviews published by John Wiley & Sons Ltd. Mass Spec Rev

THE MAKING OF A FOOTPRINT IN PROTEIN FOOTPRINTING: A REVIEW IN HONOR OF MICHAEL L. GROSS

2020-05-12T00:00

Within the past decade protein footprinting in conjunction with mass spectrometry has become a powerful and versatile means to unravel the higher order structure of proteins. Footprinting‐based approaches has demonstrated the capacity to inform on interaction sites and dynamic regions that participate in conformational changes. These findings when set in a biological perspective inform on protein folding/unfolding, protein–protein interactions, and protein–ligand interactions. In this review, we will look at the contribution of Dr. Michael L. Gross to protein footprinting approaches such as hydrogen deuterium exchange mass spectrometry and hydroxyl radical protein footprinting. This review details the development of novel footprinting methods as well as their applications to study higher order protein structure. © 2020 The Authors. Mass Spectrometry Reviews published by John Wiley & Sons Ltd. Mass Spec Rev

Parkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategies

2021-02-14T00:00

A plethora of studies indicate that iron metabolism is dysregulated in Parkinson's disease (PD). The literature reveals well-documented alterations consistent with established dogma, but also intriguing paradoxical observations requiring mechanistic dissection. An important fact is the iron loading in dopaminergic neurons of the substantia nigra pars compacta (SNpc), which are the cells primarily affected in PD. Assessment of these changes reveal increased expression of proteins critical for iron uptake, namely transferrin receptor 1 and the divalent metal transporter 1 (DMT1), and decreased expression of the iron exporter, ferroportin-1 (FPN1). Consistent with this is the activation of iron regulator protein (IRP) RNA-binding activity, which is an important regulator of iron homeostasis, with its activation indicating cytosolic iron deficiency. In fact, IRPs bind to iron-responsive elements (IREs) in the 3ꞌ untranslated region (UTR) of certain mRNAs to stabilize their half-life, while binding to the 5ꞌ UTR prevents translation. Iron loading of dopaminergic neurons in PD may occur through these mechanisms, leading to increased neuronal iron and iron-mediated reactive oxygen species (ROS) generation. The “gold standard” histological marker of PD, Lewy bodies, are mainly composed of α-synuclein, the expression of which is markedly increased in PD. Of note, an atypical IRE exists in the α-synuclein 5ꞌ UTR that may explain its up-regulation by increased iron. This dysregulation could be impacted by the unique autonomous pacemaking of dopaminergic neurons of the SNpc that engages L-type Ca⁺² channels, which imparts a bioenergetic energy deficit and mitochondrial redox stress. This dysfunction could then drive alterations in iron trafficking that attempt to rescue energy deficits such as the increased iron uptake to provide iron for key electron transport proteins. Considering the increased iron-loading in PD brains, therapies utilizing limited iron chelation have shown success. Greater therapeutic advancements should be possible once the exact molecular pathways of iron processing are dissected.

Global patterns of avian influenza A (H7): virus evolution and zoonotic threats

2019-08-05T00:00

Avian influenza viruses (AIVs) continue to impose a negative impact on animal and human health worldwide. In particular, the emergence of highly pathogenic AIV H5 and, more recently, the emergence of low pathogenic AIV H7N9 have led to enormous socioeconomical losses in the poultry industry and resulted in fatal human infections. While H5N1 remains infamous, the number of zoonotic infections with H7N9 has far surpassed those attributed to H5. Despite the clear public health concerns posed by AIV H7, it is unclear why specifically this virus subtype became endemic in poultry and emerged in humans. In this review, we bring together data on global patterns of H7 circulation, evolution and emergence in humans. Specifically, we discuss data from the wild bird reservoir, expansion and epidemiology in poultry, significant increase in their zoonotic potential since 2013 and genesis of highly pathogenic H7. In addition, we analysed available sequence data from an evolutionary perspective, demonstrating patterns of introductions into distinct geographic regions and reassortment dynamics. The integration of all aspects is crucial in the optimisation of surveillance efforts in wild birds, poultry and humans, and we emphasise the need for a One Health approach in controlling emerging viruses such as AIV H7.

H7 avian influenza virus causes infections in birds and mammals and is of pandemic concern; our review brings together data from the ecology, veterinary and human health points of view and demonstrates the importance of ‘One Heath’ in the long-term management of this virus.

Impact of nanosystems in Staphylococcus aureus biofilms treatment

2019-08-17T00:00

Staphylococcus aureus (S. aureus) is considered by the World Health Organization as a high priority pathogen for which new therapies are needed. This is particularly important for biofilm implant-associated infections once the only available treatment option implies a surgical procedure combined with antibiotic therapy. Consequently, these infections represent an economic burden for Healthcare Systems. A new strategy has emerged to tackle this problem: for small bugs, small particles. Here, we describe how nanotechnology-based systems have been studied to treat S. aureus biofilms. Their features, drawbacks and potentialities to impact the treatment of these infections are highlighted. Furthermore, we also outline biofilm models and assays required for preclinical validation of those nanosystems to smooth the process of clinical translation.

Staphylococcus aureus biofilms are a major cause for implant-associated infections. The lack of an effective treatment and the escalating numbers of antibiotic-resistance events are prompting the research toward alternative nano-based strategies.

Chromatin-dependent regulation of secondary metabolite biosynthesis in fungi: is the picture complete?

2019-06-20T00:00

Fungal secondary metabolites are small molecules that exhibit diverse biological activities exploited in medicine, industry and agriculture. Their biosynthesis is governed by co-expressed genes that often co-localize in gene clusters. Most of these secondary metabolite gene clusters are inactive under laboratory conditions, which is due to a tight transcriptional regulation. Modifications of chromatin, the complex of DNA and histone proteins influencing DNA accessibility, play an important role in this regulation. However, tinkering with well-characterised chemical and genetic modifications that affect chromatin alters the expression of only few biosynthetic gene clusters, and thus the regulation of the vast majority of biosynthetic pathways remains enigmatic. In the past, attempts to activate silent gene clusters in fungi mainly focused on histone acetylation and methylation, while in other eukaryotes many other post-translational modifications are involved in transcription regulation. Thus, how chromatin regulates the expression of gene clusters remains a largely unexplored research field. In this review, we argue that focusing on only few well-characterised chromatin modifications is significantly hampering our understanding of the chromatin-based regulation of biosynthetic gene clusters. Research on underexplored chromatin modifications and on the interplay between different modifications is timely to fully explore the largely untapped reservoir of fungal secondary metabolites.

This review focuses on the chromatin-based regulation of fungal secondary metabolite biosynthesis and argues that the incomplete picture of chromatin modifications in fungi significantly hampers the activation and exploitation of fungal secondary metabolites in medicine, industry and agriculture.

Recent trends in molecular diagnostics of yeast infections: from PCR to NGS

2019-06-03T00:00

The incidence of opportunistic yeast infections in humans has been increasing over recent years. These infections are difficult to treat and diagnose, in part due to the large number and broad diversity of species that can underlie the infection. In addition, resistance to one or several antifungal drugs in infecting strains is increasingly being reported, severely limiting therapeutic options and showcasing the need for rapid detection of the infecting agent and its drug susceptibility profile. Current methods for species and resistance identification lack satisfactory sensitivity and specificity, and often require prior culturing of the infecting agent, which delays diagnosis. Recently developed high-throughput technologies such as next generation sequencing or proteomics are opening completely new avenues for more sensitive, accurate and fast diagnosis of yeast pathogens. These approaches are the focus of intensive research, but translation into the clinics requires overcoming important challenges. In this review, we provide an overview of existing and recently emerged approaches that can be used in the identification of yeast pathogens and their drug resistance profiles. Throughout the text we highlight the advantages and disadvantages of each methodology and discuss the most promising developments in their path from bench to bedside.

The authors discuss the current status of the use of high-throughput (-omics) technologies on the diagnostics of yeast infections.

Clinical relevance of extracellular vesicles in hematological neoplasms: from liquid biopsy to cell biopsy

2020-12-09T00:00

In the era of precision medicine, liquid biopsy is becoming increasingly important in oncology. It consists in the isolation and analysis of tumor-derived biomarkers, including extracellular vesicles (EVs), in body fluids. EVs are lipid bilayer-enclosed particles, heterogeneous in size and molecular composition, released from both normal and neoplastic cells. In tumor context, EVs are valuable carriers of cancer information; in fact, their amount, phenotype and molecular cargo, including proteins, lipids, metabolites and nucleic acids, mirror nature and origin of parental cells rendering EVs appealing candidates as novel biomarkers. Translation of these new potential diagnostic tools into clinical practice could deeply revolutionize the cancer field mainly for solid tumors but for hematological neoplasms, too.

COVID-19 enters the expanding network of apolipoprotein E4-related pathologies

2021-03-10T00:00

COVID-19 incidence and case fatality rates (CFR) differ among ethnicities, stimulating efforts to pinpoint genetic factors that could explain these phenomena. In this regard, the multiallelic apolipoprotein E (APOE) gene has recently been interrogated in the UK biobank cohort, demonstrating associations of the APOE ε4/ε4 genotype with COVID-19 severity and mortality. The frequency of the ε4 allele and thus the distribution of APOE ε4/ε4 genotype may differ among populations. We have assessed APOE genotypes in 1638 Greek individuals, based on haplotypes derived from SNP rs7412 and rs429358 and found reduced frequency of ε4/ε4 compared to the British cohort. Herein we discuss this finding in relation to CFR and hypothesize on the potential mechanisms linking APOE ε4/ε4 to severe COVID-19. We postulate that the metabolic deregulation ensued by APOE4, manifested by elevated cholesterol and oxidized lipoprotein levels, may be central to heightened pneumocyte susceptibility to infection and to exaggerated lung inflammation associated with the ε4/ε4 genotype. We also discuss putative dietary and pharmacological approaches for the prevention and management of COVID-19 in APOE ε4/ε4 individuals.

DNA stability: a central design consideration for DNA data storage systems

2021-03-01T00:00

Data storage in DNA is a rapidly evolving technology that could be a transformative solution for the rising energy, materials, and space needs of modern information storage. Given that the information medium is DNA itself, its stability under different storage and processing conditions will fundamentally impact and constrain design considerations and data system capabilities. Here we analyze the storage conditions, molecular mechanisms, and stabilization strategies influencing DNA stability and pose specific design configurations and scenarios for future systems that best leverage the considerable advantages of DNA storage.

DNA has the potential to store vast amounts of data but it is subject to physical decay. In this Perspective, the authors propose that the stability of DNA should be a key consideration in how it is used for data storage.

A matter of concern – Trace element dyshomeostasis and genomic stability in neurons

2021-01-24T00:00

Neurons are post-mitotic cells in the brain and their integrity is of central importance to avoid neurodegeneration. Yet, the inability of self-replenishment of post-mitotic cells results in the need to withstand challenges from numerous stressors during life. Neurons are exposed to oxidative stress due to high oxygen consumption during metabolic activity in the brain. Accordingly, DNA damage can occur and accumulate, resulting in genome instability. In this context, imbalances in brain trace element homeostasis are a matter of concern, especially regarding iron, copper, manganese, zinc, and selenium. Although trace elements are essential for brain physiology, excess and deficient conditions are considered to impair neuronal maintenance. Besides increasing oxidative stress, DNA damage response and repair of oxidative DNA damage are affected by trace elements. Hence, a balanced trace element homeostasis is of particular importance to safeguard neuronal genome integrity and prevent neuronal loss. This review summarises the current state of knowledge on the impact of deficient, as well as excessive iron, copper, manganese, zinc, and selenium levels on neuronal genome stability.

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Post-mitotic neurons show an increased vulnerability to oxidative stress.

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Trace element dyshomeostasis impairs neuronal genome maintenance, affecting DNA damage response as well as DNA repair.

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The review summarises the effects of excessive and deficient trace element levels neuronal genome stability maintenance.

The antioxidant response in Barrett's tumorigenesis: A double-edged sword

2021-02-14T00:00

Esophageal adenocarcinoma (EAC) is the dominant form of esophageal malignancies in the United States and other industrialized countries. The incidence of EAC has been rising rapidly during the past four decades. Barrett's esophagus (BE) is the main precancerous condition for EAC, where a metaplastic columnar epithelium replaces normal squamous mucosa of the lower esophagus. The primary risk factor for BE and EAC are chronic gastroesophageal reflux disease (GERD), obesity and smoking. During the BE-dysplasia-EAC sequence, esophageal cells are under a tremendous burden of accumulating reactive oxygen species (ROS) and oxidative stress. While normal cells have intact antioxidant machinery to maintain a balanced anti-tumorigenic physiological response, the antioxidant capacity is compromised in neoplastic cells with a pro-tumorigenic development antioxidant response. The accumulation of ROS, during the neoplastic progression of the GERD-BE-EAC sequence, induces DNA damage, lipid peroxidation and protein oxidation. Neoplastic cells adapt to oxidative stress by developing a pro-tumorigenic antioxidant response that keeps oxidative damage below lethal levels while promoting tumorigenesis, progression, and resistance to therapy. In this review, we will summarize the recent findings on oxidative stress in tumorigenesis in the context of the GERD-BE-EAC process. We will discuss how EAC cells adapt to increased ROS. We will review APE1 and NRF2 signaling mechanisms in the context of EAC. Finally, we will discuss the potential clinical significance of applying antioxidants or NRF2 activators as chemoprevention and NRF2 inhibitors in treating EAC patients.

Carbohydrates great and small, from dietary fiber to sialic acids: How glycans influence the gut microbiome and affect human health

Gut microbiome composition depends heavily upon diet and has strong ties to human health. Dietary carbohydrates shape the gut microbiome by providing a potent nutrient source for particular microbes. This review explores how dietary carbohydrates in general, including individual monosaccharides and complex polysaccharides, influence the gut microbiome with subsequent effects on host health and disease. In particular, the effects of sialic acids, a prominent and influential class of monosaccharides, are discussed. Complex plant carbohydrates, such as dietary fiber, generally promote microbial production of compounds beneficial to the host while preventing degradation of host carbohydrates from colonic mucus. In contrast, simple and easily digestible sugars such as glucose are often associated with adverse effects on health and the microbiome. The monosaccharide class of sialic acids exerts a powerful but nuanced effect on gut microbiota. Sialic acid consumption (in monosaccharide form, or as part of human milk oligosaccharides or certain animal-based foods) drives the growth of organisms with sialic acid metabolism capabilities. Minor chemical modifications of Neu5Ac, the most common form of sialic acid, can alter these effects. All aspects of carbohydrate composition are therefore relevant to consider when designing dietary therapeutic strategies to alter the gut microbiome.

Renal metabolism and hypertension

2021-02-11T00:00

Hypertension is a leading risk factor for disease burden worldwide. The kidneys, which have a high specific metabolic rate, play an essential role in the long-term regulation of arterial blood pressure. In this review, we discuss the emerging role of renal metabolism in the development of hypertension. Renal energy and substrate metabolism is characterized by several important and, in some cases, unique features. Recent advances suggest that alterations of renal metabolism may result from genetic abnormalities or serve initially as a physiological response to environmental stressors to support tubular transport, which may ultimately affect regulatory pathways and lead to unfavorable cellular and pathophysiological consequences that contribute to the development of hypertension.

Hypertension is one of the most important risk factors for cardiovascular disease. The kidneys, which have a very high metabolic rate, play a fundamental role in blood pressure regulation. In this review, the authors discuss recent studies on the role of renal metabolism in the development of hypertension.

The metabolic impact of small intestinal nutrient sensing

2021-02-10T00:00

The gastrointestinal tract maintains energy and glucose homeostasis, in part through nutrient-sensing and subsequent signaling to the brain and other tissues. In this review, we highlight the role of small intestinal nutrient-sensing in metabolic homeostasis, and link high-fat feeding, obesity, and diabetes with perturbations in these gut-brain signaling pathways. We identify how lipids, carbohydrates, and proteins, initiate gut peptide release from the enteroendocrine cells through small intestinal sensing pathways, and how these peptides regulate food intake, glucose tolerance, and hepatic glucose production. Lastly, we highlight how the gut microbiota impact small intestinal nutrient-sensing in normal physiology, and in disease, pharmacological and surgical settings. Emerging evidence indicates that the molecular mechanisms of small intestinal nutrient sensing in metabolic homeostasis have physiological and pathological impact as well as therapeutic potential in obesity and diabetes.

The gastrointestinal tract participates in maintaining metabolic homeostasis in part through nutrient-sensing and subsequent gut-brain signalling. Here the authors review the role of small intestinal nutrient-sensing in regulation of energy intake and systemic glucose metabolism, and link high-fat diet, obesity and diabetes with perturbations in these pathways.

A review framework of how earthquakes trigger volcanic eruptions

2021-02-12T00:00

It is generally accepted that tectonic earthquakes may trigger volcanic activity, although the underlying mechanisms are poorly constrained. Here, we review current knowledge, and introduce a novel framework to help characterize earthquake-triggering processes. This framework outlines three parameters observable at volcanoes, namely magma viscosity, open- or closed-system degassing and the presence or absence of an active hydrothermal system. Our classification illustrates that most types of volcanoes may be seismically-triggered, though require different combinations of volcanic and seismic conditions, and triggering is unlikely unless the system is primed for eruption. Seismically-triggered unrest is more common, and particularly associated with hydrothermal systems.

This review dives deep into how earthquakes affect volcanoes, specifically into the relation between tectonic seismic activity and subsequent eruptions. Activity may increase in any volcanic setting in the 2–5 years following an earthquake, and especially at volcanic centres featuring vigorous hydrothermal activity.

Role of oxidative stress in the dysfunction of the placental endothelial nitric oxide synthase in preeclampsia

2021-01-19T00:00

Preeclampsia (PE) is a multifactorial pregnancy disease, characterized by new-onset gestational hypertension with (or without) proteinuria or end-organ failure, exclusively observed in humans. It is a leading cause of maternal morbidity affecting 3–7% of pregnant women worldwide. PE pathophysiology could result from abnormal placentation due to a defective trophoblastic invasion and an impaired remodeling of uterine spiral arteries, leading to a poor adaptation of utero-placental circulation. This would be associated with hypoxia/reoxygenation phenomena, oxygen gradient fluctuations, altered antioxidant capacity, oxidative stress, and reduced nitric oxide (NO) bioavailability. This results in part from the reaction of NO with the radical anion superoxide (O₂^•−), which produces peroxynitrite ONOO^-, a powerful pro-oxidant and inflammatory agent. Another mechanism is the progressive inhibition of the placental endothelial nitric oxide synthase (eNOS) by oxidative stress, which results in eNOS uncoupling via several events such as a depletion of the eNOS substrate L-arginine due to increased arginase activity, an oxidation of the eNOS cofactor tetrahydrobiopterin (BH4), or eNOS post-translational modifications (for instance by S-glutathionylation). The uncoupling of eNOS triggers a switch of its activity from a NO-producing enzyme to a NADPH oxidase-like system generating O₂^•−, thereby potentiating ROS production and oxidative stress. Moreover, in PE placentas, eNOS could be post-translationally modified by lipid peroxidation-derived aldehydes such as 4-oxononenal (ONE) a highly bioreactive agent, able to inhibit eNOS activity and NO production. This review summarizes the dysfunction of placental eNOS evoked by oxidative stress and lipid peroxidation products, and the potential consequences on PE pathogenesis.

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Physiological ROS production is enhanced during pregnancy.

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eNOS is one of the main target of oxidative stress in PE placenta.

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eNOS is S-glutathionylated in PE placentas.

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eNOS is modified by lipid oxidation products in PE placentas.

DJ-1: A promising therapeutic candidate for ischemia-reperfusion injury

2021-01-30T00:00

DJ-1 is a multifaceted protein with pleiotropic functions that has been implicated in multiple diseases, ranging from neurodegeneration to cancer and ischemia-reperfusion injury. Ischemia is a complex pathological state arising when tissues and organs do not receive adequate levels of oxygen and nutrients. When the blood flow is restored, significant damage occurs over and above that of ischemia alone and is termed ischemia-reperfusion injury. Despite great efforts in the scientific community to ameliorate this pathology, its complex nature has rendered it challenging to obtain satisfactory treatments that translate to the clinic. In this review, we will describe the recent findings on the participation of the protein DJ-1 in the pathophysiology of ischemia-reperfusion injury, firstly introducing the features and functions of DJ-1 and, successively highlighting the therapeutic potential of the protein.

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DJ-1 has been shown to confer protection in ischemia-reperfusion injury models.

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DJ-1 protection relies on the activation of antioxidant signaling pathways.

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DJ-1 regulates mitochondrial homeostasis during ischemia and reperfusion.

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DJ-1 seems to modulate ion homeostasis during ischemia and reperfusion.

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DJ-1 may represent a promising therapeutic target for ischemia-reperfusion injury.

CXCR4 in Waldenström’s Macroglobulinema: chances and challenges

2020-12-03T00:00

It is one of the major aims in cancer research to improve our understanding of the underlying mechanisms which initiate and maintain tumor growth and to translate these findings into novel clinical diagnostic and therapeutic concepts with the ultimate goal to improve patient care. One of the greater success stories in this respect has been Waldenström’s Macroglobulinemia (WM), which is an incurable B-cell neoplasm characterized by serum monoclonal immunoglobulin M (IgM) and clonal lymphoplasmacytic cells infiltrating the bone marrow. Recent years have succeeded to describe the molecular landscape of WM in detail, highlighting two recurrently mutated genes, the MYD88 and the CXCR4 genes: MYD88 with an almost constant and recurrent point mutation present in over 90% of patients and CXCR4 with over 40 different mutations in the coding region affecting up to 40% of patients. Intriguingly, both mutations are activating mutations leading in the case of CXCR4 to an indelible activation and perpetual signaling of the chemokine receptor. These data have shed light on the essential role of CXCR4 in this disease and have paved the way to use these findings for predicting treatment response to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and novel therapeutic approaches in WM, which might be transferable to other related CXCR4 positive diseases. Well known for its central role in cancer progression and distribution, CXCR4 is highlighted in this review with regard to its biology, prognostic and predictive relevance and therapeutic implications in WM.

Ubiquitin-dependent and -independent functions of OTULIN in cell fate control and beyond

2020-12-07T00:00

Ubiquitination, and its control by deubiquitinating enzymes (DUBs), mediates protein stability, function, signaling and cell fate. The ovarian tumor (OTU) family DUB OTULIN (FAM105B) exclusively cleaves linear (Met1-linked) poly-ubiquitin chains and plays important roles in auto-immunity, inflammation and infection. OTULIN regulates Met1-linked ubiquitination downstream of tumor necrosis factor receptor 1 (TNFR1), toll-like receptor (TLR) and nucleotide-binding and oligomerization domain-containing protein 2 (NOD2) receptor activation and interacts with the Met1 ubiquitin-specific linear ubiquitin chain assembly complex (LUBAC) E3 ligase. However, despite extensive research efforts, the receptor and cytosolic roles of OTULIN and the distributions of multiple Met1 ubiquitin-associated E3-DUB complexes in the regulation of cell fate still remain controversial and unclear. Apart from that, novel ubiquitin-independent OTULIN functions have emerged highlighting an even more complex role of OTULIN in cellular homeostasis. For example, OTULIN interferes with endosome-to-plasma membrane trafficking and the OTULIN-related pseudo-DUB OTULINL (FAM105A) resides at the endoplasmic reticulum (ER). Here, we discuss how OTULIN contributes to cell fate control and highlight novel ubiquitin-dependent and -independent functions.

Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances

2020-10-29T00:00

Bruton’s tyrosine kinase (BTK) inhibitor is a promising novel agent that has potential efficiency in B-cell malignancies. It took approximately 20 years from target discovery to new drug approval. The first-in-class drug ibrutinib creates possibilities for an era of chemotherapy-free management of B-cell malignancies, and it is so popular that gross sales have rapidly grown to more than 230 billion dollars in just 6 years, with annual sales exceeding 80 billion dollars; it also became one of the five top-selling medicines in the world. Numerous clinical trials of BTK inhibitors in cancers were initiated in the last decade, and ~73 trials were intensively announced or updated with extended follow-up data in the most recent 3 years. In this review, we summarized the significant milestones in the preclinical discovery and clinical development of BTK inhibitors to better understand the clinical and commercial potential as well as the directions being taken. Furthermore, it also contributes impactful lessons regarding the discovery and development of other novel therapies.

The role of E3 ubiquitin ligases in the development and progression of glioblastoma

2021-01-11T00:00

Despite recent advances in our understanding of the disease, glioblastoma (GB) continues to have limited treatment options and carries a dismal prognosis for patients. Efforts to stratify this heterogeneous malignancy using molecular classifiers identified frequent alterations in targetable proteins belonging to several pathways including the receptor tyrosine kinase (RTK) and mitogen-activated protein kinase (MAPK) signalling pathways. However, these findings have failed to improve clinical outcomes for patients. In almost all cases, GB becomes refractory to standard-of-care therapy, and recent evidence suggests that disease recurrence may be associated with a subpopulation of cells known as glioma stem cells (GSCs). Therefore, there remains a significant unmet need for novel therapeutic strategies. E3 ubiquitin ligases are a family of >700 proteins that conjugate ubiquitin to target proteins, resulting in an array of cellular responses, including DNA repair, pro-survival signalling and protein degradation. Ubiquitin modifications on target proteins are diverse, ranging from mono-ubiquitination through to the formation of polyubiquitin chains and mixed chains. The specificity in substrate tagging and chain elongation is dictated by E3 ubiquitin ligases, which have essential regulatory roles in multiple aspects of brain cancer pathogenesis. In this review, we begin by briefly summarising the histological and molecular classification of GB. We comprehensively describe the roles of E3 ubiquitin ligases in RTK and MAPK, as well as other, commonly altered, oncogenic and tumour suppressive signalling pathways in GB. We also describe the role of E3 ligases in maintaining glioma stem cell populations and their function in promoting resistance to ionizing radiation (IR) and chemotherapy. Finally, we consider how our knowledge of E3 ligase biology may be used for future therapeutic interventions in GB, including the use of blood–brain barrier permeable proteolysis targeting chimeras (PROTACs).

Deubiquitylases in developmental ubiquitin signaling and congenital diseases

2020-12-17T00:00

Metazoan development from a one-cell zygote to a fully formed organism requires complex cellular differentiation and communication pathways. To coordinate these processes, embryos frequently encode signaling information with the small protein modifier ubiquitin, which is typically attached to lysine residues within substrates. During ubiquitin signaling, a three-step enzymatic cascade modifies specific substrates with topologically unique ubiquitin modifications, which mediate changes in the substrate’s stability, activity, localization, or interacting proteins. Ubiquitin signaling is critically regulated by deubiquitylases (DUBs), a class of ~100 human enzymes that oppose the conjugation of ubiquitin. DUBs control many essential cellular functions and various aspects of human physiology and development. Recent genetic studies have identified mutations in several DUBs that cause developmental disorders. Here we review principles controlling DUB activity and substrate recruitment that allow these enzymes to regulate ubiquitin signaling during development. We summarize key mechanisms of how DUBs control embryonic and postnatal differentiation processes, highlight developmental disorders that are caused by mutations in particular DUB members, and describe our current understanding of how these mutations disrupt development. Finally, we discuss how emerging tools from human disease genetics will enable the identification and study of novel congenital disease-causing DUBs.

Organoid-based modeling of intestinal development, regeneration, and repair

2020-11-18T00:00

The intestinal epithelium harbors a remarkable adaptability to undergo injury-induced repair. A key part of the regenerative response is the transient reprogramming of epithelial cells into a fetal-like state, which drives uniform proliferation, tissue remodeling, and subsequent restoration of the homeostatic state. In this review, we discuss how Wnt and YAP signaling pathways control the intestinal repair response and the transitioning of cell states, in comparison with the process of intestinal development. Furthermore, we highlight how organoid-based applications have contributed to the characterization of the mechanistic principles and key players that guide these developmental and regenerative events.

Anomalous transport due to Weyl fermions in the chiral antiferromagnets Mn₃X, X = Sn, Ge

2021-01-25T00:00

The recent discoveries of strikingly large zero-field Hall and Nernst effects in antiferromagnets Mn₃X (X = Sn, Ge) have brought the study of magnetic topological states to the forefront of condensed matter research and technological innovation. These effects are considered fingerprints of Weyl nodes residing near the Fermi energy, promoting Mn₃X (X = Sn, Ge) as a fascinating platform to explore the elusive magnetic Weyl fermions. In this review, we provide recent updates on the insights drawn from experimental and theoretical studies of Mn₃X (X = Sn, Ge) by combining previous reports with our new, comprehensive set of transport measurements of high-quality Mn₃Sn and Mn₃Ge single crystals. In particular, we report magnetotransport signatures specific to chiral anomalies in Mn₃Ge and planar Hall effect in Mn₃Sn, which have not yet been found in earlier studies. The results summarized here indicate the essential role of magnetic Weyl fermions in producing the large transverse responses in the absence of magnetization.

The large anomalous Hall (AHE) and anomalous Nernst effects (ANE) in antiferromagnets Mn₃Sn/Mn₃Ge are considered fingerprints of Weyl nodes residing near the Fermi energy. Here, the authors review the results from previous studies combining with new transport measurements on Mn₃Sn/Mn₃Ge single crystals, suggesting the essential role of magnetic Weyl fermions in explaining the AHE and ANE.

Perspectives on skeletal muscle stem cells

2021-01-29T00:00

Skeletal muscle has remarkable regeneration capabilities, mainly due to its resident muscle stem cells (MuSCs). In this review, we introduce recently developed technologies and the mechanistic insights they provide to the understanding of MuSC biology, including the re-definition of quiescence and G_alert states. Additionally, we present recent studies that link MuSC function with cellular heterogeneity, highlighting the complex regulation of self-renewal in regeneration, muscle disorders and aging. Finally, we discuss MuSC metabolism and its role, as well as the multifaceted regulation of MuSCs by their niche. The presented conceptual advances in the MuSC field impact on our general understanding of stem cells and their therapeutic use in regenerative medicine.

Skeletal muscle has a remarkable regenerative capacity, which can largely be attributed to resident muscle stem cells (MuSCs). Here, the authors review the molecular mechanisms regulating MuSC quiescence, activation and proliferation, how these processes are regulated by the stem cell niche, and the role of MuSCs in neuromuscular diseases.

Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities

2021-01-07T00:00

Neurodegenerative diseases are characterised by progressive damage to the nervous system including the selective loss of vulnerable populations of neurons leading to motor symptoms and cognitive decline. Despite millions of people being affected worldwide, there are still no drugs that block the neurodegenerative process to stop or slow disease progression. Neuronal death in these diseases is often linked to the misfolded proteins that aggregate within the brain (proteinopathies) as a result of disease-related gene mutations or abnormal protein homoeostasis. There are two major degradation pathways to rid a cell of unwanted or misfolded proteins to prevent their accumulation and to maintain the health of a cell: the ubiquitin–proteasome system and the autophagy–lysosomal pathway. Both of these degradative pathways depend on the modification of targets with ubiquitin. Aging is the primary risk factor of most neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. With aging there is a general reduction in proteasomal degradation and autophagy, and a consequent increase of potentially neurotoxic protein aggregates of β-amyloid, tau, α-synuclein, SOD1 and TDP-43. An often over-looked yet major component of these aggregates is ubiquitin, implicating these protein aggregates as either an adaptive response to toxic misfolded proteins or as evidence of dysregulated ubiquitin-mediated degradation driving toxic aggregation. In addition, non-degradative ubiquitin signalling is critical for homoeostatic mechanisms fundamental for neuronal function and survival, including mitochondrial homoeostasis, receptor trafficking and DNA damage responses, whilst also playing a role in inflammatory processes. This review will discuss the current understanding of the role of ubiquitin-dependent processes in the progressive loss of neurons and the emergence of ubiquitin signalling as a target for the development of much needed new drugs to treat neurodegenerative disease.

Depression, obesity and their comorbidity during pregnancy: effects on the offspring’s mental and physical health

2020-07-06T00:00

Depression and obesity represent two of the most common complications during pregnancy and are associated with severe health risks for both the mother and the child. Although several studies have analysed the individual effects of depression or obesity on the mothers and their children, the effects associated with the co-occurrence of both disorders have so far been poorly investigated. The relationship between depression and obesity is very complex and it is still unclear whether maternal depression leads to obesity or vice versa. It is well known that the intrauterine environment plays an important role in mediating the effects of both depression and obesity in the mother on the fetal programming, increasing the child’s risk to develop negative outcomes.

Organoid systems to study the human female reproductive tract and pregnancy

2020-06-03T00:00

Both the proper functioning of the female reproductive tract (FRT) and normal placental development are essential for women’s health, wellbeing, and pregnancy outcome. The study of the FRT in humans has been challenging due to limitations in the in vitro and in vivo tools available. Recent developments in 3D organoid technology that model the different regions of the FRT include organoids of the ovaries, fallopian tubes, endometrium and cervix, as well as placental trophoblast. These models are opening up new avenues to investigate the normal biology and pathology of the FRT. In this review, we discuss the advances, potential, and limitations of organoid cultures of the human FRT.

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Ubiquitin signaling in cell cycle control and tumorigenesis

2020-10-31T00:00

Cell cycle progression is a tightly regulated process by which DNA replicates and cell reproduces. The major driving force underlying cell cycle progression is the sequential activation of cyclin-dependent kinases (CDKs), which is achieved in part by the ubiquitin-mediated proteolysis of their cyclin partners and kinase inhibitors (CKIs). In eukaryotic cells, two families of E3 ubiquitin ligases, anaphase-promoting complex/cyclosome and Skp1-Cul1-F-box protein complex, are responsible for ubiquitination and proteasomal degradation of many of these CDK regulators, ensuring cell cycle progresses in a timely and precisely regulated manner. In the past couple of decades, accumulating evidence have demonstrated that the dysregulated cell cycle transition caused by inefficient proteolytic control leads to uncontrolled cell proliferation and finally results in tumorigenesis. Based upon this notion, targeting the E3 ubiquitin ligases involved in cell cycle regulation is expected to provide novel therapeutic strategies for cancer treatment. Thus, a better understanding of the diversity and complexity of ubiquitin signaling in cell cycle regulation will shed new light on the precise control of the cell cycle progression and guide anticancer drug development.

CRISPR technologies and the search for the PAM-free nuclease

2021-01-22T00:00

The ever-expanding set of CRISPR technologies and their programmable RNA-guided nucleases exhibit remarkable flexibility in DNA targeting. However, this flexibility comes with an ever-present constraint: the requirement for a protospacer adjacent motif (PAM) flanking each target. While PAMs play an essential role in self/nonself discrimination by CRISPR-Cas immune systems, this constraint has launched a far-reaching expedition for nucleases with relaxed PAM requirements. Here, we review ongoing efforts toward realizing PAM-free nucleases through natural ortholog mining and protein engineering. We also address potential consequences of fully eliminating PAM recognition and instead propose an alternative nuclease repertoire covering all possible PAM sequences.

One of the key limitations of CRISPR-Cas-based genome editing techniques is the PAM dependency. Here, the authors review ongoing efforts towards realizing PAM-free nucleases, address potential consequences of eliminating PAM recognition, and propose an alternative nuclease repertoire covering all possible PAM sequences.

Neuronal cell life, death, and axonal degeneration as regulated by the BCL-2 family proteins

2020-11-08T00:00

Axonal degeneration and neuronal cell death are fundamental processes in development and contribute to the pathology of neurological disease in adults. Both processes are regulated by BCL-2 family proteins which orchestrate the permeabilization of the mitochondrial outer membrane (MOM). MOM permeabilization (MOMP) results in the activation of pro-apoptotic molecules that commit neurons to either die or degenerate. With the success of small-molecule inhibitors targeting anti-apoptotic BCL-2 proteins for the treatment of lymphoma, we can now envision the use of inhibitors of apoptosis with exquisite selectivity for BCL-2 family protein regulation of neuronal apoptosis in the treatment of nervous system disease. Critical to this development is deciphering which subset of proteins is required for neuronal apoptosis and axon degeneration, and how these two different outcomes are separately regulated. Moreover, noncanonical BCL-2 family protein functions unrelated to the regulation of MOMP, including impacting necroptosis and other modes of cell death may reveal additional potential targets and/or confounders. This review highlights our current understanding of BCL-2 family mediated neuronal cell death and axon degeneration, while identifying future research questions to be resolved to enable regulating neuronal survival pharmacologically.

Oligodendrocyte lineage cells and depression

2020-11-03T00:00

Depression is a common mental illness, affecting more than 300 million people worldwide. Decades of investigation have yielded symptomatic therapies for this disabling condition but have not led to a consensus about its pathogenesis. There are data to support several different theories of causation, including the monoamine hypothesis, hypothalamic–pituitary–adrenal axis changes, inflammation and immune system alterations, abnormalities of neurogenesis and a conducive environmental milieu. Research in these areas and others has greatly advanced the current understanding of depression; however, there are other, less widely known theories of pathogenesis. Oligodendrocyte lineage cells, including oligodendrocyte progenitor cells and mature oligodendrocytes, have numerous important functions, which include forming myelin sheaths that enwrap central nervous system axons, supporting axons metabolically, and mediating certain forms of neuroplasticity. These specialized glial cells have been implicated in psychiatric disorders such as depression. In this review, we summarize recent findings that shed light on how oligodendrocyte lineage cells might participate in the pathogenesis of depression, and we discuss new approaches for targeting these cells as a novel strategy to treat depression.

Advances in the field of intranasal oxytocin research: lessons learned and future directions for clinical research

2020-08-17T00:00

Reports on the modulatory role of the neuropeptide oxytocin on social cognition and behavior have steadily increased over the last two decades, stimulating considerable interest in its psychiatric application. Basic and clinical research in humans primarily employs intranasal application protocols. This approach assumes that intranasal administration increases oxytocin levels in the central nervous system via a direct nose-to-brain route, which in turn acts upon centrally-located oxytocin receptors to exert its behavioral effects. However, debates have emerged on whether intranasally administered oxytocin enters the brain via the nose-to-brain route and whether this route leads to functionally relevant increases in central oxytocin levels. In this review we outline recent advances from human and animal research that provide converging evidence for functionally relevant effects of the intranasal oxytocin administration route, suggesting that direct nose-to-brain delivery underlies the behavioral effects of oxytocin on social cognition and behavior. Moreover, advances in previously debated methodological issues, such as pre-registration, reproducibility, statistical power, interpretation of non-significant results, dosage, and sex differences are discussed and integrated with suggestions for the next steps in translating intranasal oxytocin into psychiatric applications.

Discontinuation of antidepressants after remission with antidepressant medication in major depressive disorder: a systematic review and meta-analysis

2020-07-23T00:00

A significant clinical issue encountered after a successful acute major depressive disorder (MDD) treatment is the relapse of depressive symptoms. Although continuing maintenance therapy with antidepressants is generally recommended, there is no established protocol on whether or not it is necessary to prescribe the antidepressant used to achieve remission. In this meta-analysis, the risk of relapse and treatment failure when either continuing with the same drug used to achieved remission or switching to a placebo was assessed in several clinically significant subgroups. The pooled odds ratio (OR) (±95% confidence intervals (CI)) was calculated using a random effects model. Across 40 studies (n = 8890), the relapse rate was significantly lower in the antidepressant group than the placebo group by about 20% (OR = 0.38, CI: 0.33–0.43, p < 0.00001; 20.9% vs 39.7%). The difference in the relapse rate between the antidepressant and placebo groups was greater for tricyclics (25.3%; OR = 0.30, CI: 0.17–0.50, p < 0.00001), SSRIs (21.8%; OR = 0.33, CI: 0.28–0.38, p < 0.00001), and other newer agents (16.0%; OR = 0.44, CI: 0.36–0.54, p < 0.00001) in that order, while the effect size of acceptability was greater for SSRIs than for other antidepressants. A flexible dose schedule (OR = 0.30, CI: 0.23–0.48, p < 0.00001) had a greater effect size than a fixed dose (OR = 0.41, CI: 0.36–0.48, p < 0.00001) in comparison to placebo. Even in studies assigned after continuous treatment for more than 6 months after remission, the continued use of antidepressants had a lower relapse rate than the use of a placebo (OR = 0.40, CI: 0.29–0.55, p < 0.00001; 20.2% vs 37.2%). The difference in relapse rate was similar from a maintenance period of 6 months (OR = 0.41, CI: 0.35–0.48, p < 0.00001; 19.6% vs 37.6%) to over 1 year (OR = 0.35, CI: 0.29–0.41, p < 0.00001; 19.9% vs 39.8%). The all-cause dropout of antidepressant and placebo groups was 43% and 58%, respectively, (OR = 0.47, CI: 0.40–0.55, p < 0.00001). The tolerability rate was ~4% for both groups. The rate of relapse (OR = 0.32, CI: 0.18–0.64, p = 0.0010, 41.0% vs 66.7%) and all-cause dropout among adolescents was higher than in adults. To prevent relapse and treatment failure, maintenance therapy, and careful attention for at least 6 months after remission is recommended. SSRIs are well-balanced agents, and flexible dose adjustments are more effective for relapse prevention.

Re-definition and supporting evidence toward Fanconi Anemia as a mitochondrial disease: Prospects for new design in clinical management

2021-01-07T00:00

Fanconi anemia (FA) has been investigated since early studies based on two definitions, namely defective DNA repair and proinflammatory condition. The former definition has built up the grounds for FA diagnosis as excess sensitivity of patients’ cells to xenobiotics as diepoxybutane and mitomycin C, resulting in typical chromosomal abnormalities. Another line of studies has related FA phenotype to a prooxidant state, as detected by both in vitro and ex vivo studies. The discovery that the FA group G (FANCG) protein is found in mitochondria (Mukhopadhyay et al., 2006) has been followed by an extensive line of studies providing evidence for multiple links between other FA gene products and mitochondrial dysfunction. The fact that FA proteins are encoded by nuclear, not mitochondrial DNA does not prevent these proteins to hamper mitochondrial function, as it is recognized that most mitochondrial proteins are of nuclear origin. This body of evidence supporting a central role of mitochondrial dysfunction, along with redox imbalance in FA, should lead to the re-definition of FA as a mitochondrial disease. A body of literature has demonstrated the beneficial effects of mitochondrial cofactors, such as α-lipoic acid, coenzyme Q10, and carnitine on patients affected by mitochondrial diseases. Altogether, this re-definition of FA as a mitochondrial disease and the prospect use of mitochondrial nutrients may open new gateways toward mitoprotective strategies for FA patients. These strategies are expected to mitigate the mitochondrial dysfunction and prooxidant state in FA patients, and potentially protect transplanted FA patients from post-transplantation malignancies.

The Met1-linked ubiquitin machinery in inflammation and infection

2021-01-20T00:00

Ubiquitination is an essential post-translational modification that regulates most cellular processes. The assembly of ubiquitin into polymeric chains by E3 ubiquitin ligases underlies the pleiotropic functions ubiquitin chains regulate. Ubiquitin chains assembled via the N-terminal methionine, termed Met1-linked ubiquitin chains or linear ubiquitin chains, have emerged as essential signalling scaffolds that regulate pro-inflammatory responses, anti-viral interferon responses, cell death and xenophagy of bacterial pathogens downstream of innate immune receptors. Met1-linked ubiquitin chains are exclusively assembled by the linear ubiquitin chain assembly complex, LUBAC, and are disassembled by the deubiquitinases OTULIN and CYLD. Genetic defects that perturb the regulation of Met1-linked ubiquitin chains causes severe immune-related disorders, illustrating their potent signalling capacity. Here, we review the current knowledge about the cellular machinery that conjugates, recognises, and disassembles Met1-linked ubiquitin chains, and discuss the function of this unique posttranslational modification in regulating inflammation, cell death and immunity to pathogens.

Resilin-mimetics as a smart biomaterial platform for biomedical applications

2021-01-08T00:00

Intrinsically disordered proteins have dramatically changed the structure–function paradigm of proteins in the 21^st century. Resilin is a native elastic insect protein, which features intrinsically disordered structure, unusual multi-stimuli responsiveness and outstanding resilience. Advances in computational techniques, polypeptide synthesis methods and modular protein engineering routines have led to the development of novel resilin-like polypeptides (RLPs) including modular RLPs, expanding their applications in tissue engineering, drug delivery, bioimaging, biosensors, catalysis and bioelectronics. However, how the responsive behaviour of RLPs is encoded in the amino acid sequence level remains elusive. This review summarises the milestones of RLPs, and discusses the development of modular RLP-based biomaterials, their current applications, challenges and future perspectives. A perspective of future research is that sequence and responsiveness profiling of RLPs can provide a new platform for the design and development of new modular RLP-based biomaterials with programmable structure, properties and functions.

Advances made in synthesis and analytical techniques has allowed the exploration and mimicry of natural materials. Resilin-mimetics have emerged from this advance as a biomaterial with a range of potential applications. Here, the authors review the history and current research on resilin-mimetics, providing a future perspective.

Mechanisms of muscle atrophy and hypertrophy: implications in health and disease

2021-01-12T00:00

Skeletal muscle is the protein reservoir of our body and an important regulator of glucose and lipid homeostasis. Consequently, the growth or the loss of muscle mass can influence general metabolism, locomotion, eating and respiration. Therefore, it is not surprising that excessive muscle loss is a bad prognostic index of a variety of diseases ranging from cancer, organ failure, infections and unhealthy ageing. Muscle function is influenced by different quality systems that regulate the function of contractile proteins and organelles. These systems are controlled by transcriptional dependent programs that adapt muscle cells to environmental and nutritional clues. Mechanical, oxidative, nutritional and energy stresses, as well as growth factors or cytokines modulate signaling pathways that, ultimately, converge on protein and organelle turnover. Novel insights that control and orchestrate such complex network are continuously emerging and will be summarized in this review. Understanding the mechanisms that control muscle mass will provide therapeutic targets for the treatment of muscle loss in inherited and non-hereditary diseases and for the improvement of the quality of life during ageing.

Loss of muscle mass is associated with ageing and with a number of diseases such as cancer. Here, the authors review the signaling pathways that modulate protein synthesis and degradation and gain or loss of muscle mass, and discuss therapeutic implications and future directions for the field.

COVID-19 vaccines: where we stand and challenges ahead

2021-01-21T00:00

In the eleven months elapsed since the identification of the SARS-CoV-2 virus and its genome, an exceptional effort by the scientific community has led to the development of over 300 vaccine projects. Over 40 are now undergoing clinical evaluation, ten of these are in Phase III clinical trials, three of them have ended Phase III with positive results. A few of these new vaccines are being approved for emergency use. Existing data suggest that new vaccine candidates may be instrumental in protecting individuals and reducing the spread of pandemic. The conceptual and technological platforms exploited are diverse, and it is likely that different vaccines will show to be better suited to distinct groups of the human population. Moreover, it remains to be elucidated whether and to what extent the capacity of vaccines under evaluation and of unrelated vaccines such as BCG can increase immunological fitness by training innate immunity to SARS-CoV-2 and pathogen-agnostic protection. Due to the short development time and the novelty of the technologies adopted, these vaccines will be deployed with several unresolved issues that only the passage of time will permit to clarify. Technical problems connected with the production of billions of doses and ethical ones connected with the availably of these vaccines also in the poorest countries, are imminent challenges facing us. It is our tenet that in the long run more than one vaccine will be needed to ensure equitable global access, protection of diverse subjects and immunity against viral variants.

Recommendations for vaccination in multiple myeloma: a consensus of the European Myeloma Network

2020-08-19T00:00

Vaccination is one of the most successful medical interventions that has saved the life of millions of people. Vaccination is particularly important in patients with multiple myeloma, who have an increased risk of infections due to the disease-inherent immune suppression, and because of the immune suppressive effects of therapy. Hence, all appropriate measures should be exploited, to elicit an effective immune response to common pathogens like influenza, pneumococci, varicella zoster virus, and to those bacteria and viruses (haemophilus influenzae, meningococci, and hepatitis) that frequently may pose a significant risk to patients with multiple myeloma. Patients after autologous, and specifically after allogeneic transplantation have severely reduced antibody titers, and therefore require a broader spectrum of vaccinations. Response to vaccination in myeloma often is less vigorous than in the general population, mandating either measurement of the postvaccination antibody titers and/or repeating the vaccination. Here, we compile the existing data on vaccination in multiple myeloma and provide recommendations for clinical practice.

Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis

2020-07-09T00:00

Myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) is characterized by cytopenias, marrow fibrosis, constitutional symptoms, extramedullary hematopoiesis, splenomegaly, and shortened survival. Constitutive activation of the janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in MF leads to cell proliferation, inhibition of cell death, and clonal expansion of myeloproliferative malignant cells. Fedratinib is a selective oral JAK2 inhibitor recently approved in the United States for treatment of adult patients with intermediate-2 or high-risk MF. In mouse models of JAK2V617F-driven myeloproliferative disease, fedratinib blocked phosphorylation of STAT5, increased survival, and improved MF-associated disease features, including reduction of white blood cell counts, hematocrit, splenomegaly, and fibrosis. Fedratinib exerts off-target inhibitory activity against bromodomain-containing protein 4 (BRD4); combination JAK/STAT and BRD4 inhibition was shown to synergistically block NF-kB hyperactivation and inflammatory cytokine production, attenuating disease burden and reversing bone marrow fibrosis in animal models of MPNs. In patients, fedratinib is rapidly absorbed and dosed once daily (effective half-life 41 h). Fedratinib showed robust clinical activity in JAK-inhibitor-naïve patients and in patients with MF who were relapsed, refractory, or intolerant to prior ruxolitinib therapy. Fedratinib is effective regardless of JAK2 mutation status. Onset of spleen and symptom responses are typically seen within the first 1–2 months of treatment. The most common adverse events (AEs) with fedratinib are grades 1–2 gastrointestinal events, which are most frequent during early treatment and decrease over time. Treatment discontinuation due to hematologic AEs in clinical trials was uncommon (~3%). Suspected cases of Wernicke’s encephalopathy were reported during fedratinib trials in ~1% of patients; thiamine levels should be monitored before and during fedratinib treatment as medically indicated. Phase III trials are ongoing to assess fedratinib effects on long-term safety, efficacy, and overall survival. The recent approval of fedratinib provides a much-needed addition to the limited therapeutic options available for patients with MF.

Bacteriocins as a new generation of antimicrobials: toxicity aspects and regulations

2020-09-02T00:00

In recent decades, bacteriocins have received substantial attention as antimicrobial compounds. Although bacteriocins have been predominantly exploited as food preservatives, they are now receiving increased attention as potential clinical antimicrobials and as possible immune-modulating agents. Infections caused by antibiotic-resistant bacteria have been declared as a global threat to public health. Bacteriocins represent a potential solution to this worldwide threat due to their broad- or narrow-spectrum activity against antibiotic-resistant bacteria. Notably, despite their role in food safety as natural alternatives to chemical preservatives, nisin remains the only bacteriocin legally approved by regulatory agencies as a food preservative. Moreover, insufficient data on the safety and toxicity of bacteriocins represent a barrier against the more widespread use of bacteriocins by the food and medical industry. Here, we focus on the most recent trends relating to the application of bacteriocins, their toxicity and impacts.

Antimicrobial activity, gastrointestinal bihaviour and toxicity of bacteriocins.

Host cell death during infection with Chlamydia: a double-edged sword

2020-09-08T00:00

The phylum Chlamydiae constitutes a group of obligate intracellular bacteria that infect a remarkably diverse range of host species. Some representatives are significant pathogens of clinical or veterinary importance. For instance, Chlamydia trachomatis is the leading infectious cause of blindness and the most common bacterial agent of sexually transmitted diseases. Chlamydiae are exceptionally dependent on their eukaryotic host cells as a consequence of their developmental biology. At the same time, host cell death is an integral part of the chlamydial infection cycle. It is therefore not surprising that the bacteria have evolved exquisite and versatile strategies to modulate host cell survival and death programs to their advantage. The recent introduction of tools for genetic modification of Chlamydia spp., in combination with our increasing awareness of the complexity of regulated cell death in eukaryotic cells, and in particular of its connections to cell-intrinsic immunity, has revived the interest in this virulence trait. However, recent advances also challenged long-standing assumptions and highlighted major knowledge gaps. This review summarizes current knowledge in the field and discusses possible directions for future research, which could lead us to a deeper understanding of Chlamydia’s virulence strategies and may even inspire novel therapeutic approaches.

A comprehensive review that highlights recent advances and major knowledge gaps in our understanding of the diverse mechanisms and roles of pathogen-mediated host cell death modulation during infection with the obligate intracellular pathogen Chlamydia trachomatis and its relatives.

Uptake, recognition and responses to peptidoglycan in the mammalian host

2020-09-08T00:00

Microbiota, and the plethora of signalling molecules that they generate, are a major driving force that underlies a striking range of inter-individual physioanatomic and behavioural consequences for the host organism. Among the bacterial effectors, one finds peptidoglycan, the major constituent of the bacterial cell surface. In the steady-state, fragments of peptidoglycan are constitutively liberated from bacterial members of the gut microbiota, cross the gut epithelial barrier and enter the host system. The fate of these peptidoglycan fragments, and the outcome for the host, depends on the molecular nature of the peptidoglycan, as well the cellular profile of the recipient tissue, mechanism of cell entry, the expression of specific processing and recognition mechanisms by the cell, and the local immune context. At the target level, physiological processes modulated by peptidoglycan are extremely diverse, ranging from immune activation to small molecule metabolism, autophagy and apoptosis. In this review, we bring together a fragmented body of literature on the kinetics and dynamics of peptidoglycan interactions with the mammalian host, explaining how peptidoglycan functions as a signalling molecule in the host under physiological conditions, how it disseminates within the host, and the cellular responses to peptidoglycan.

A comprehensive review of the diverse mechanisms acting in the mammalian host to facilitate the uptake, biodistribution, processing and recognition of the major bacterial cell wall constituent, peptidoglycan, a key microbiome effector molecule influencing host physiology during health and disease.

Bacterial cell proliferation: from molecules to cells

2020-09-29T00:00

Bacterial cell proliferation is highly efficient, both because bacteria grow fast and multiply with a low failure rate. This efficiency is underpinned by the robustness of the cell cycle and its synchronization with cell growth and cytokinesis. Recent advances in bacterial cell biology brought about by single-cell physiology in microfluidic chambers suggest a series of simple phenomenological models at the cellular scale, coupling cell size and growth with the cell cycle. We contrast the apparent simplicity of these mechanisms based on the addition of a constant size between cell cycle events (e.g. two consecutive initiation of DNA replication or cell division) with the complexity of the underlying regulatory networks. Beyond the paradigm of cell cycle checkpoints, the coordination between the DNA and division cycles and cell growth is largely mediated by a wealth of other mechanisms. We propose our perspective on these mechanisms, through the prism of the known crosstalk between DNA replication and segregation, cell division and cell growth or size. We argue that the precise knowledge of these molecular mechanisms is critical to integrate the diverse layers of controls at different time and space scales into synthetic and verifiable models.

Newly characterized simple principles that describe how bacterial cells grow and divide at the cellular scale need to be related with the underlying complex and interwoven molecular mechanisms.

Ubiquitination in the regulation of inflammatory cell death and cancer

2021-01-11T00:00

The ubiquitin system is complex, multifaceted, and is crucial for the modulation of a vast number of cellular processes. Ubiquitination is tightly regulated at different levels by a range of enzymes including E1s, E2s, and E3s, and an array of DUBs. The UPS directs protein degradation through the proteasome, and regulates a wide array of cellular processes including transcription and epigenetic factors as well as key oncoproteins. Ubiquitination is key to the dynamic regulation of programmed cell death. Notably, the TNF signaling pathway is controlled by competing ubiquitin conjugation and deubiquitination, which governs both proteasomal degradation and signaling complex formation. In the inflammatory response, ubiquitination is capable of both activating and dampening inflammasome activation through the control of either protein stability, complex formation, or, in some cases, directly affecting receptor activity. In this review, we discuss the enzymes and targets in the ubiquitin system that regulate fundamental cellular processes regulating cell death, and inflammation, as well as disease consequences resulting from their dysregulation. Finally, we highlight several pre-clinical and clinical compounds that regulate ubiquitin system enzymes, with the aim of restoring homeostasis and ameliorating diseases.

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Bacteriocins as a new generation of antimicrobials: toxicity aspects and regulations

Host cell death during infection with Chlamydia: a double-edged sword

Uptake, recognition and responses to peptidoglycan in the mammalian host

Bacterial cell proliferation: from molecules to cells

Ubiquitination in the regulation of inflammatory cell death and cancer

Anomalous transport due to Weyl fermions in the chiral antiferromagnets Mn₃X, X = Sn, Ge