Structural diversity in echinocandin biosynthesis: the impact of oxidation steps and approaches toward an evolutionary explanation

2017 ◽  
Vol 72 (1-2) ◽  
pp. 1-20 ◽  
Author(s):  
Wolfgang Hüttel
Keyword(s):  
Secondary Metabolism ◽  
Current Knowledge ◽  
Structural Diversity ◽  
Special Focus ◽  
Oxidation Reactions ◽  
Metabolic Diversity ◽  
Comprehensive Overview ◽  
Single Organism ◽  
The Impact ◽  
Best Fit

AbstractEchinocandins are an important group of cyclic non-ribosomal peptides with strong antifungal activity produced by filamentous fungi from Aspergillaceae and Leotiomycetes. Their structure is characterized by numerous hydroxylated non-proteinogenic amino acids. Biosynthetic clusters discovered in the last years contain up to six oxygenases, all of which are involved in amino acid modifications. Especially, variations in the oxidation pattern induced by these enzymes account for a remarkable structural diversity among the echinocandins. This review provides an overview of the current knowledge of echinocandin biosynthesis with a special focus on diversity-inducing oxidation steps. The emergence of metabolic diversity is further discussed on the basis of a comprehensive overview of the structurally characterized echinocandins, their producer strains and biosynthetic clusters. For the pneumocandins, echinocandins produced byGlarea lozoyensis, the formation of metabolic diversity in a single organism is analyzed. It is compared to two common models for the evolution of secondary metabolism: the ‘target-based’ approach and the ‘diversity-based’ model. Whereas the early phase of pneumocandin biosynthesis supports the target-based model, the diversity-inducing late steps and most oxidation reactions best fit the diversity-based approach. Moreover, two types of diversity-inducing steps can be distinguished. Although incomplete hydroxylation is a common phenomenon in echinocandin production and secondary metabolite biosynthesis in general, the incorporation of diverse hydroxyprolines at position 6 is apparently a unique feature of pneumocandin biosynthesis, which stands in stark contrast to the strict selectivity found in echinocandin biosynthesis by Aspergillaceae. The example of echinocandin biosynthesis shows that the existing models for the evolution of secondary metabolism can be well applied to parts of the pathway; however, thus far, there is no comprehensive theory that could explain the entire biosynthesis.

scholarly journals Echinocandins: structural diversity, biosynthesis, and development of antimycotics

2020 ◽  
Vol 105 (1) ◽  
pp. 55-66
Author(s):  
Wolfgang Hüttel
Keyword(s):  
Isotope Labeling ◽  
Current Knowledge ◽  
Complex Structure ◽  
Hydrolytic Stability ◽  
Structural Diversity ◽  
Gene Clusters ◽  
Special Focus ◽  
Key Points ◽  
Invasive Mycosis ◽  
History Of

Abstract Echinocandins are a clinically important class of non-ribosomal antifungal lipopeptides produced by filamentous fungi. Due to their complex structure, which is characterized by numerous hydroxylated non-proteinogenic amino acids, echinocandin antifungal agents are manufactured semisynthetically. The development of optimized echinocandin structures is therefore closely connected to their biosynthesis. Enormous efforts in industrial research and development including fermentation, classical mutagenesis, isotope labeling, and chemical synthesis eventually led to the development of the active ingredients caspofungin, micafungin, and anidulafungin, which are now used as first-line treatments against invasive mycosis. In the last years, echinocandin biosynthetic gene clusters have been identified, which allowed for the elucidation but also engineering of echinocandin biosynthesis on the molecular level. After a short description of the history of echinocandin research, this review provides an overview of the current knowledge of echinocandin biosynthesis with a special focus of the diverse structural elements, their biosynthetic background, and structure−activity relationships. Key points • Complex and highly oxidized lipopeptides produced by fungi. • Crucial in the design of drugs: side chain, solubility, and hydrolytic stability. • Genetic methods for engineering biosynthesis have recently become available.

The Oxford Handbook of Hope

2017 ◽  
Keyword(s):  
Current Knowledge ◽  
Physical And Mental Health ◽  
Comprehensive Overview ◽  
Future Directions ◽  
Theoretical Perspectives ◽  
The Many ◽  
The Impact ◽  
Made In

The Oxford Handbook of Hope provides a comprehensive overview of current knowledge regarding the science and practice of hope. Hope has long been a topic of interest to philosophers and the general public, but it was only in recent decades that hope became a focus of psychological science. Rick Snyder defined hope as a cognitive trait that helps individuals to identify and pursue goals and consists of two components: pathways, the perceived capacity to identify strategies necessary to achieve goals, and agency, the willpower or motivation to pursue those pathways to achieve goals. Hope has become one of most robust and promising topics in the burgeoning field of positive psychology. This book reviews the progress that has been made in the past 25 years regarding the origins and influence of hope. Topics covered include current theoretical perspectives on how best to define hope and how it is distinct from related constructs, current best practices for measuring and quantifying hope, interventions and strategies for promoting hope across different settings and the lifespan, the impact that hope has on many dimensions and domains of physical and mental health, and the many ways and contexts in which hope promotes resilience and positive functioning. Experts in the field both review what is currently known about the role of hope in different domains and identify topics and questions that can help to guide the next decade of research. The handbook concludes with a collaborative vision on the future directions of the science of hope.

scholarly journals Impact of Housing Environment on the Immune System in Chickens: A Review

Animals ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1138 ◽  
Author(s):  
Tanja Hofmann ◽  
Sonja S. Schmucker ◽  
Werner Bessei ◽  
Michael Grashorn ◽  
Volker Stefanski
Keyword(s):  
Immune System ◽  
Allostatic Load ◽  
Current Knowledge ◽  
Future Research ◽  
Poultry Production ◽  
Negative Consequences ◽  
Comprehensive Overview ◽  
Housing Environment ◽  
Wide Range ◽  
The Impact

During their lifespan, chickens are confronted with a wide range of acute and chronic stressors in their housing environment that may threaten their welfare and health by modulating the immune system. Especially chronic stressful conditions can exceed the individual’s allostatic load, with negative consequences for immunity. A fully functional immune system is mandatory for health and welfare and, consequently, also for high productivity and safe animal products. This review provides a comprehensive overview of the impact of housing form, light regime as well as aerial ammonia and hydrogen sulfide concentrations on the immune system in chickens. Certain housing conditions are clearly associated with immunological alterations which potentially impair the success of vaccinations or affect disease susceptibility. Such poor conditions counteract sustainable poultry production. This review also outlines current knowledge gaps and provides recommendations for future research.

scholarly journals The Mammalian Metaorganism: A Holistic View on How Microbes of All Kingdoms and Niches Shape Local and Systemic Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Solveig Runge ◽  
Stephan Patrick Rosshart
Keyword(s):  
Current Knowledge ◽  
Biologically Active ◽  
Comprehensive Overview ◽  
Holistic View ◽  
Systemic Immunity ◽  
Major Interest ◽  
Microbiome Research ◽  
Epithelial Barriers ◽  
And Function ◽  
The Impact

The field of microbiome research has developed rapidly over the past decades and has become a topic of major interest to basic, preclinical, and clinical research, the pharmaceutical industry as well as the general public. The microbiome is a complex and diverse ecosystem and defined as the collection of all host-associated microorganisms and their genes. It is acquired through vertical transmission and environmental exposure and includes microbes of all kingdoms: bacteria, archaea, prokaryotic and eukaryotic viruses, fungi, protozoa, and the meiofauna. These microorganisms co-evolved with their respective hosts over millions of years, thereby establishing a mutually beneficial, symbiotic relationship on all epithelial barriers. Thus, the microbiome plays a pivotal role in virtually every aspect of mammalian physiology, particularly in the development, homeostasis, and function of the immune system. Consequently, the combination of the host genome and the microbial genome, together referred to as the metagenome, largely drives the mammalian phenotype. So far, the majority of studies have unilaterally focused on the gastrointestinal bacterial microbiota. However, recent work illustrating the impact of viruses, fungi, and protozoa on host immunity urges us towards a holistic view of the mammalian microbiome and the appreciation for its non-bacterial kingdoms. In addition, the importance of microbiota on epithelial barriers other than the gut as well as their systemic effects via microbially-derived biologically active compounds is increasingly recognized. Here, we want to provide a brief but comprehensive overview of the most important findings and the current knowledge on how microbes of all kingdoms and microbial niches shape local and systemic immunity in health and disease.

scholarly journals Ciliary Genes in Renal Cystic Diseases

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 907 ◽  
Author(s):  
Anna Adamiok-Ostrowska ◽  
Agnieszka Piekiełko-Witkowska
Keyword(s):  
Transient Receptor Potential ◽  
Current Knowledge ◽  
Apical Cell ◽  
Receptor Potential ◽  
Renal Diseases ◽  
Special Focus ◽  
Type I ◽  
Altered Expression ◽  
Transient Receptor ◽  
The Impact

Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as mechanosensors of nephron cells, responding to fluid movements by triggering signal transduction. The impaired functioning of primary cilia leads to formation of cysts which in turn contribute to development of diverse renal diseases, including kidney ciliopathies and renal cancer. Here, we review current knowledge on the role of ciliary genes in kidney ciliopathies and renal cell carcinoma (RCC). Special focus is given on the impact of mutations and altered expression of ciliary genes (e.g., encoding polycystins, nephrocystins, Bardet-Biedl syndrome (BBS) proteins, ALS1, Oral-facial-digital syndrome 1 (OFD1) and others) in polycystic kidney disease and nephronophthisis, as well as rare genetic disorders, including syndromes of Joubert, Meckel-Gruber, Bardet-Biedl, Senior-Loken, Alström, Orofaciodigital syndrome type I and cranioectodermal dysplasia. We also show that RCC and classic kidney ciliopathies share commonly disturbed genes affecting cilia function, including VHL (von Hippel-Lindau tumor suppressor), PKD1 (polycystin 1, transient receptor potential channel interacting) and PKD2 (polycystin 2, transient receptor potential cation channel). Finally, we discuss the significance of ciliary genes as diagnostic and prognostic markers, as well as therapeutic targets in ciliopathies and cancer.

scholarly journals Perinatal Nutritional and Metabolic Pathways: Early Origins of Chronic Lung Diseases

2021 ◽  
Vol 8 ◽  
Author(s):  
Celien Kuiper-Makris ◽  
Jaco Selle ◽  
Eva Nüsken ◽  
Jörg Dötsch ◽  
Miguel A. Alejandre Alcazar
Keyword(s):  
Lung Diseases ◽  
Maternal Obesity ◽  
Current Knowledge ◽  
Oxygen Toxicity ◽  
Experimental Models ◽  
Nutrient Sensing ◽  
Matrix Remodeling ◽  
Comprehensive Overview ◽  
Chronic Lung Diseases ◽  
The Impact

Lung development is not completed at birth, but expands beyond infancy, rendering the lung highly susceptible to injury. Exposure to various influences during a critical window of organ growth can interfere with the finely-tuned process of development and induce pathological processes with aberrant alveolarization and long-term structural and functional sequelae. This concept of developmental origins of chronic disease has been coined as perinatal programming. Some adverse perinatal factors, including prematurity along with respiratory support, are well-recognized to induce bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease that is characterized by arrest of alveolar and microvascular formation as well as lung matrix remodeling. While the pathogenesis of various experimental models focus on oxygen toxicity, mechanical ventilation and inflammation, the role of nutrition before and after birth remain poorly investigated. There is accumulating clinical and experimental evidence that intrauterine growth restriction (IUGR) as a consequence of limited nutritive supply due to placental insufficiency or maternal malnutrition is a major risk factor for BPD and impaired lung function later in life. In contrast, a surplus of nutrition with perinatal maternal obesity, accelerated postnatal weight gain and early childhood obesity is associated with wheezing and adverse clinical course of chronic lung diseases, such as asthma. While the link between perinatal nutrition and lung health has been described, the underlying mechanisms remain poorly understood. There are initial data showing that inflammatory and nutrient sensing processes are involved in programming of alveolarization, pulmonary angiogenesis, and composition of extracellular matrix. Here, we provide a comprehensive overview of the current knowledge regarding the impact of perinatal metabolism and nutrition on the lung and beyond the cardiopulmonary system as well as possible mechanisms determining the individual susceptibility to CLD early in life. We aim to emphasize the importance of unraveling the mechanisms of perinatal metabolic programming to develop novel preventive and therapeutic avenues.

scholarly journals Significance of indeterminate pulmonary nodules in resectable pancreatic adenocarcinoma—a review

2021 ◽  
Author(s):  
Li Lian Kuan ◽  
Ashley R. Dennison ◽  
Giuseppe Garcea
Keyword(s):  
Overall Survival ◽  
Pancreatic Adenocarcinoma ◽  
Median Overall Survival ◽  
Current Knowledge ◽  
Pulmonary Nodules ◽  
Preoperative Imaging ◽  
Significant Finding ◽  
Comprehensive Overview ◽  
Significant Difference ◽  
Clinical Dilemma

Abstract Background The clinical significance of indeterminate pulmonary nodules (IPN) in patients with resectable pancreatic adenocarcinoma (PDAC) is unknown. The rate of detection on IPN has risen due to enhanced staging investigations to determine resectability. IPNs detected on preoperative imaging represent a clinical dilemma and complicate decision-making. Currently, there are no recommendations on the management of IPN. This review provides a comprehensive overview of the current knowledge on the natural history of IPN detected among patients with resectable PDAC. Methods A systematic review based on a search in Medline and Embase databases was performed. All clinical studies evaluating the significance of IPN in patients with resectable PDAC were included. PRISMA guidelines were followed. Results Five studies met the inclusion criteria. The total patient population was 761. The prevalence of IPN reported ranged from 18 to 71%. The median follow-up duration was 17 months. The median overall survival was 19 months. Patients with pre-operative IPN which subsequently progressed to clinically recognizable pulmonary metastases, ranged from 1.5 to 16%. Four studies found that there was no significant difference in median overall survival in patients with or without IPNs. Conclusion This is a first review on the significance of IPN in patients with resectable PDAC. The preoperative presence of IPN does not demonstrate an association with overall survival after surgery. The identification of IPN is a significant finding however it should not preclude patients with resectable PDAC from undergoing curative resection.

scholarly journals Comprehensive Overview of Sleep Disorders in Patients with Chronic Liver Disease

2021 ◽  
Vol 11 (2) ◽  
pp. 142
Author(s):  
Oana-Mihaela Plotogea ◽  
Madalina Ilie ◽  
Simona Bungau ◽  
Alexandru Laurentiu Chiotoroiu ◽  
Ana Maria Alexandra Stanescu ◽  
...  
Keyword(s):  
Sleep Disorders ◽  
Daily Practice ◽  
Chronic Liver ◽  
Asian Countries ◽  
Chronic Liver Diseases ◽  
Comprehensive Overview ◽  
The Usa ◽  
The Impact ◽  
Reliable Methods

The impact of sleep disorders (SDs) on patients with chronic liver diseases (CLD) is tremendous. SDs are frequently encountered among these patients and interfere with their quality of life. This review aims to present the data available so far about the prevalence, phenotypes, and proposed pathophysiological mechanisms of SDs in CLD. Moreover, we proposed to search the literature regarding the most reliable methods to assess SDs and the possible therapeutic options in patients with CLD. The main results of this review show that when it comes to prevalence, the percentages reported vary widely between studies performed among populations from the USA or Europe and those coming from Asian countries. Furthermore, it has been proven that SDs may also be present in the absence of neurocognitive disorders attributable to hepatic encephalopathy (HE), which contradicts traditional suppositions where SDs were considered part of the clinical scenario of HE. Currently, there are no specific recommendations or protocols to assess SDs in CLD patients and data about the therapeutic management are limited. Taking into consideration their impact, a protocol for diagnosing and managing SDs should be developed and included in the daily practice of hepatologists.

What Determines Fiscal Deficits in Europe? The Impact and Interaction of EMU Membership, Fiscal Rules, Fiscal Councils and Creative Accounting

2020 ◽  
Vol 71 (1) ◽  
pp. 15-41
Author(s):  
Dominik Maltritz ◽  
Sebastian Wüste
Keyword(s):  
Fiscal Rules ◽  
Special Focus ◽  
Annual Data ◽  
Budget Balance ◽  
Fiscal Deficits ◽  
Eu Countries ◽  
Creative Accounting ◽  
Stock Flow ◽  
The Impact

AbstractWe search for drivers of fiscal deficits in Europe using a data panel containing annual data of 27 EU countries in the years 1991–2012. Our special focus is on the influence of fiscal rules as well as on fiscal councils, i. e. institutions that may help to reduce deficits and enforce fiscal rules by advising governments. We distinguish between internal fiscal rules and external rules that result from EMU membership. In addition, we consider the impact of “creative accounting”, i. e. measures that help to circumvent fiscal rules, which we approximate by so called stock-flow-adjustments. We especially analyze the interactive influence of the mentioned variables on the budget balance.

scholarly journals Hypoxia, Acidification and Inflammation: Partners in Crime in Parkinson’s Disease Pathogenesis?

Immuno ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 78-90
Author(s):  
Johannes Burtscher ◽  
Grégoire P. Millet
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Current Knowledge ◽  
Cell Types ◽  
Brain Cell ◽  
Special Focus ◽  
Molecular Alterations ◽  
Research Fields

Like in other neurodegenerative diseases, protein aggregation, mitochondrial dysfunction, oxidative stress and neuroinflammation are hallmarks of Parkinson’s disease (PD). Differentiating characteristics of PD include the central role of α-synuclein in the aggregation pathology, a distinct vulnerability of the striato-nigral system with the related motor symptoms, as well as specific mitochondrial deficits. Which molecular alterations cause neurodegeneration and drive PD pathogenesis is poorly understood. Here, we summarize evidence of the involvement of three interdependent factors in PD and suggest that their interplay is likely a trigger and/or aggravator of PD-related neurodegeneration: hypoxia, acidification and inflammation. We aim to integrate the existing knowledge on the well-established role of inflammation and immunity, the emerging interest in the contribution of hypoxic insults and the rather neglected effects of brain acidification in PD pathogenesis. Their tight association as an important aspect of the disease merits detailed investigation. Consequences of related injuries are discussed in the context of aging and the interaction of different brain cell types, in particular with regard to potential consequences on the vulnerability of dopaminergic neurons in the substantia nigra. A special focus is put on the identification of current knowledge gaps and we emphasize the importance of related insights from other research fields, such as cancer research and immunometabolism, for neurodegeneration research. The highlighted interplay of hypoxia, acidification and inflammation is likely also of relevance for other neurodegenerative diseases, despite disease-specific biochemical and metabolic alterations.

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