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.

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.

New Insights into the Pathogenesis, Risk Factors, and Treatment of Portal Vein Thrombosis in Patients with Cirrhosis

2020 ◽  
Vol 46 (06) ◽  
pp. 673-681 ◽  
Author(s):  
Oana Nicoară-Farcău ◽  
Guillem Soy ◽  
Marta Magaz ◽  
Anna Baiges ◽  
Fanny Turon ◽  
...  
Keyword(s):  
Risk Factors ◽  
Portal Vein ◽  
Portal Vein Thrombosis ◽  
Current Knowledge ◽  
Current Evidence ◽  
Special Focus ◽  
Vein Thrombosis ◽  
Frequent Event ◽  
Intrahepatic Portosystemic Shunt ◽  
History Of

AbstractPortal vein thrombosis (PVT) is a frequent event in patients with cirrhosis regardless of etiology. Notwithstanding the commonality of the problem, the pathophysiology and risk factors for PVT in cirrhosis are largely unknown. The clinical impact of PVT in the natural history of cirrhosis is unclear, indications for PVT treatment are not well defined, and treatment recommendations are based on experts' opinion and consensus only. Therefore, this review aims to summarize current knowledge of mechanisms and risk factors for PVT development and assess the current evidence of PVT management, with a special focus on strategies of anticoagulation and transjugular intrahepatic portosystemic shunt placement.

Tanaka Kinuyo

2018 ◽  
Keyword(s):  
Industrial Development ◽  
Japanese Woman ◽  
Cultural Construction ◽  
Public Image ◽  
Special Focus ◽  
Japanese History ◽  
Female Subjectivity ◽  
Japanese Cinema ◽  
Close Analysis ◽  
History Of

This is the first book in English dedicated to the actress and director Tanaka Kinuyo. Praised as amongst the greatest actors in the history of Japanese cinema, Tanaka’s career spanned the industrial development of cinema - from silent to sound, monochrome to colour. Alongside featuring in films by Ozu, Mizoguchi, Naruse and Kurosawa, Tanaka was also the only Japanese woman filmmaker between 1953 and 1962, and her films tackled distinctly feminine topics such as prostitution and breast cancer. Because her career overlaps with a transformative period in Japan, especially for women, this close analysis of her fascinating life and work offers new perspectives into the Japanese history of women and classical era of national cinema. The first half of the book focuses on Tanaka as actress and analyses the elements and meanings associated with her star image, and her powerful embodiment of diverse, at times contradictory, ideological discourses. The second half is dedicated to Tanaka as director and explores her public image as filmmaker and her depiction of gender and sexuality against the national history in order to reflect on her role and style as author. With a special focus on the melodrama genre and on the sociopolitical and economic contexts of film production, the book offers a revision of theories of stardom, authorship, and women’s cinema. In examining Tanaka’s iconic reification of femininities in relation to politics, national identity, and memory, the chapters shed light on the cultural construction of female subjectivity and sexuality in Japanese popular culture.

Malygina, N. (2018). Andrey Platonov and literary Moscow: А. К. Voronsky, A. M. Gorky, В. А. Pilnyak, B. L. Pasternak, Artyom Vesyoly, S. F. Budantsev, V. S. Grossman. Moscow; St. Petersburg: Nestor-Istoriya. (In Russ.)

2020 ◽  
pp. 290-293
Author(s):  
E. V. Sharygina (Novikova) ◽  
V. I. Novikov
Keyword(s):  
Complex Structure ◽  
Proletarian Literature ◽  
Progressive Ideal ◽  
History Of ◽  
Literary Period

Malygina’s book portrays Andrey Platonov in the context of the literary period in which he was active. Malygina also summarizes the history of the journal Krasnaya Nov, the Krug Publishers, and the Pereval Group. While depicted as particularly close to Pilnyak due to his expressionist tendencies, Platonov, however, remained faithful to the utopian ideal of ‘proletarian literature’ and reserved tongue-incheek comments for Soviet literary aristocrats. Although a fi   ce critic of Soviet reality, Platonov cherished his own ‘Soviet project’ – he envisaged a truly revolutionary, progressive ideal of a genuinely democratic nature. The literary period in question is shown to have a complex structure, unyielding to ideological abstractions.

Paleontology and stratigraphy of Middle Eocene rock units in the southern Green River and Uinta Basins, Wyoming and Utah

2017 ◽  
Vol 4 ◽  
pp. 1-53 ◽  
Author(s):  
Paul Murphey ◽  
K.E. Townsend ◽  
Anthony Friscia ◽  
James Westgate ◽  
Emmett Evanoff ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Middle Eocene ◽  
Green River Basin ◽  
Green River ◽  
Scientific Exploration ◽  
History Of ◽  
Climatic History ◽  
Field Excursion ◽  
Land Mammal ◽  
Bridger Formation

The Bridger Formation is restricted to the Green River Basin in southwest Wyoming, and the Uinta and Duchesne River Formations are located in the Uinta Basin in Utah. These three rock units and their diverse fossil assemblages are of great scientific importance and historic interest to vertebrate paleontologists. Notably, they are also the stratotypes from oldest to youngest for the three middle Eocene North American Land Mammal Ages—the Bridgerian, Uintan, and Duchesnean. The fossils and sediments of these formations provide a critically important record of biotic, environmental, and climatic history spanning approximately 10 million years (49 to 39 Ma). This article provides a detailed field excursion through portions of the Green River and Uinta Basins that focuses on locations of geologic, paleontologic, and historical interest. In support of the field excursion, we also provide a review of current knowledge of these formations with emphasis on lithostratigraphy, biochronology, depositional, and paleoenvironmental history, and the history of scientific exploration.

Improving the Efficacy of Anticancer Drugs via Encapsulation and Acoustic Release

2018 ◽  
Vol 18 (10) ◽  
pp. 857-880 ◽  
Author(s):  
Salma E. Ahmed ◽  
Nahid Awad ◽  
Vinod Paul ◽  
Hesham G. Moussa ◽  
Ghaleb A. Husseini
Keyword(s):  
Drug Delivery ◽  
Drug Release ◽  
Drug Delivery Systems ◽  
Delivery Systems ◽  
Special Focus ◽  
Nano Drug Delivery ◽  
Medical Researchers ◽  
History Of ◽  
Overall Performance ◽  
Enhanced Stability

Conventional chemotherapeutics lack the specificity and controllability, thus may poison healthy cells while attempting to kill cancerous ones. Newly developed nano-drug delivery systems have shown promise in delivering anti-tumor agents with enhanced stability, durability and overall performance; especially when used along with targeting and triggering techniques. This work traces back the history of chemotherapy, addressing the main challenges that have encouraged the medical researchers to seek a sanctuary in nanotechnological-based drug delivery systems that are grafted with appropriate targeting techniques and drug release mechanisms. A special focus will be directed to acoustically triggered liposomes encapsulating doxorubicin.

scholarly journals L2HGDH Missense Variant in a Cat with L-2-Hydroxyglutaric Aciduria

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 682
Author(s):  
Matthias Christen ◽  
Nils Janzen ◽  
Anne Fraser ◽  
Adrian C. Sewell ◽  
Vidhya Jagannathan ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Genetic Defect ◽  
Clinical Signs ◽  
Missense Variant ◽  
Microcytic Anemia ◽  
Abnormal Behavior ◽  
Functional Candidate Gene ◽  
History Of ◽  
The Brain ◽  
Hydroxyglutaric Acid

A 7-month-old, spayed female, domestic longhair cat with L-2-hydroxyglutaric aciduria (L-2-HGA) was investigated. The aim of this study was to investigate the clinical signs, metabolic changes and underlying genetic defect. The owner of the cat reported a 4-month history of multiple paroxysmal seizure-like episodes, characterized by running around the house, often in circles, with abnormal behavior, bumping into obstacles, salivating and often urinating. The episodes were followed by a period of disorientation and inappetence. Neurological examination revealed an absent bilateral menace response. Routine blood work revealed mild microcytic anemia but biochemistry, ammonia, lactate and pre- and post-prandial bile acids were unremarkable. MRI of the brain identified multifocal, bilaterally symmetrical and T2-weighted hyperintensities within the prosencephalon, mesencephalon and metencephalon, primarily affecting the grey matter. Urinary organic acids identified highly increased levels of L-2-hydroxyglutaric acid. The cat was treated with the anticonvulsants levetiracetam and phenobarbitone and has been seizure-free for 16 months. We sequenced the genome of the affected cat and compared the data to 48 control genomes. L2HGDH, coding for L-2-hydroxyglutarate dehydrogenase, was investigated as the top functional candidate gene. This search revealed a single private protein-changing variant in the affected cat. The identified homozygous variant, XM_023255678.1:c.1301A>G, is predicted to result in an amino acid change in the L2HGDH protein, XP_023111446.1:p.His434Arg. The available clinical and biochemical data together with current knowledge about L2HGDH variants and their functional impact in humans and dogs allow us to classify the p.His434Arg variant as a causative variant for the observed neurological signs in this cat.

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.

scholarly journals Respiratory Syncytial Virus Immunoprophylaxis with Palivizumab: 12-Year Observational Study of Usage and Outcomes in Canada

2021 ◽  
Author(s):  
Ian Mitchell ◽  
Abby Li ◽  
Candice L. Bjornson ◽  
Krista L. Lanctot ◽  
Bosco A. Paes ◽  
...  
Keyword(s):  
Risk Factors ◽  
Respiratory Syncytial Virus ◽  
Burden Of Illness ◽  
Respiratory Illness ◽  
Smoking Exposure ◽  
Key Points ◽  
Rsv Infection ◽  
History Of ◽  
Syncytial Virus ◽  
Airway Anomalies

Objective This study aimed to evaluate palivizumab (PVZ) use, trends in indications, and outcomes of respiratory illness hospitalizations (RIH) and respiratory syncytial virus hospitalizations (RSVH). Study Design It involves a large, Canadian prospective (2005–2017) observational multicenter study of children at high risk for RSV infection. Results A total of 25,003 infants (56.3% male) were enrolled at 32 sites; 109,579 PVZ injections were administered. Indications included: prematurity (63.3%); “miscellaneous” (17.8%); hemodynamically significant congenital heart disease (10.5%); bronchopulmonary dysplasia/chronic lung disease (8.4%). The “miscellaneous” group increased over time (4.4% in 2005–2006 to 22.5% in 2016–2017) and included: trisomy 21, airway anomalies, pulmonary disorders, cystic fibrosis, neurological impairments, immunocompromised, cardiac aged >2 years, multiple conditions, and a residual “unclassified” group. Adherence measured by expected versus actual doses plus correct interdose interval was 64.7%. A total of 2,054 RIH occurred (6.9%); 198 (9.6%) required intubation. Three hundred thirty-seven hospitalized children were RSV-positive (overall RSVH 1.6%). Risk factors for RSVH included having siblings, attending daycare, family history of atopy, smoking exposure, and crowded household. Infants with 5 risk factors were 9.0 times (95% CI or confidence interval 4.4–18.2; p < 0.0005) more likely to have RSVH than infants without risk factors. Three adverse events occurred; none were fatal. Conclusion Results are relevant to both clinicians and decision-makers. We confirmed the safety of PVZ. Use of PVZ increased steadily for children with miscellaneous conditions and medical complexity. Medical and social factors pose a risk for severe RIH and RSVH with accompanying burden of illness. A vaccine that protects against RSV is urgently required. Key Points

ExpanDrogram: Dynamic Visualization of Big Data Segmentation over Time

2021 ◽  
Vol 13 (2) ◽  
pp. 1-27
Author(s):  
A. Khalemsky ◽  
R. Gelbard
Keyword(s):  
Big Data ◽  
Visual Presentation ◽  
Trend Detection ◽  
Dynamic Visualization ◽  
Segmentation Process ◽  
Key Points ◽  
Wide Range ◽  
History Of ◽  
The Individual ◽  
Over Time

In dynamic and big data environments the visualization of a segmentation process over time often does not enable the user to simultaneously track entire pieces. The key points are sometimes incomparable, and the user is limited to a static visual presentation of a certain point. The proposed visualization concept, called ExpanDrogram, is designed to support dynamic classifiers that run in a big data environment subject to changes in data characteristics. It offers a wide range of features that seek to maximize the customization of a segmentation problem. The main goal of the ExpanDrogram visualization is to improve comprehensiveness by combining both the individual and segment levels, illustrating the dynamics of the segmentation process over time, providing “version control” that enables the user to observe the history of changes, and more. The method is illustrated using different datasets, with which we demonstrate multiple segmentation parameters, as well as multiple display layers, to highlight points such as new trend detection, outlier detection, tracking changes in original segments, and zoom in/out for more/less detail. The datasets vary in size from a small one to one of more than 12 million records.

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