scholarly journals Cold Adaptation in Antarctic Notothenioids: Comparative Transcriptomics Reveals Novel Insights in the Peculiar Role of Gills and Highlights Signatures of Cobalamin Deficiency

2021 ◽  
Vol 22 (4) ◽  
pp. 1812
Author(s):  
Federico Ansaloni ◽  
Marco Gerdol ◽  
Valentina Torboli ◽  
Nicola Reinaldo Fornaini ◽  
Samuele Greco ◽  
...  
Keyword(s):  
Large Scale ◽  
De Novo ◽  
Ammonia Excretion ◽  
Cobalamin Deficiency ◽  
Antarctic Species ◽  
Distinctive Features ◽  
Antarctic Notothenioids ◽  
Eleginops Maclovinus ◽  
Antarctic Waters ◽  
Evolutionary Success

Far from being devoid of life, Antarctic waters are home to Cryonotothenioidea, which represent one of the fascinating cases of evolutionary adaptation to extreme environmental conditions in vertebrates. Thanks to a series of unique morphological and physiological peculiarities, which include the paradigmatic case of loss of hemoglobin in the family Channichthyidae, these fish survive and thrive at sub-zero temperatures. While some of the distinctive features of such adaptations have been known for decades, our knowledge of their genetic and molecular bases is still limited. We generated a reference de novo assembly of the icefish Chionodraco hamatus transcriptome and used this resource for a large-scale comparative analysis among five red-blooded Cryonotothenioidea, the sub-Antarctic notothenioid Eleginops maclovinus and seven temperate teleost species. Our investigation targeted the gills, a tissue of primary importance for gaseous exchange, osmoregulation, ammonia excretion, and its role in fish immunity. One hundred and twenty genes were identified as significantly up-regulated in Antarctic species and surprisingly shared by red- and white-blooded notothenioids, unveiling several previously unreported molecular players that might have contributed to the evolutionary success of Cryonotothenioidea in Antarctica. In particular, we detected cobalamin deficiency signatures and discussed the possible biological implications of this condition concerning hematological alterations and the heavy parasitic loads typically observed in all Cryonotothenioidea.

Multiple independent reduction or loss of antifreeze trait in low Antarctic and sub-Antarctic notothenioid fishes

2015 ◽  
Vol 28 (1) ◽  
pp. 17-28 ◽  
Author(s):  
Tshoanelo Miya ◽  
Ofer Gon ◽  
Monica Mwale ◽  
C.-H. Christina Cheng
Keyword(s):  
Phylogenetic Trees ◽  
Evolutionary History ◽  
Thermal Hysteresis ◽  
Falkland Islands ◽  
Marion Island ◽  
Antarctic Species ◽  
Antifreeze Glycoprotein ◽  
Antarctic Notothenioids ◽  
Antarctic Waters ◽  
The Status

AbstractAntifreeze glycoprotein (AFGP) in Antarctic notothenioids presumably evolved once at the base of the notothenioid radiation in the Southern Ocean. Some species closely related to the endemic Antarctic notothenioids occur in non-freezing sub-Antarctic waters where antifreeze protection is unnecessary. We examined the antifreeze trait (phenotype and genotype) of these sub-Antarctic species to help infer their evolutionary history and origin. The status of the AFGP genotype (AFGP coding sequences in DNA) and/or phenotype (serum thermal hysteresis) varies widely, from being undetectable in Dissostichus eleginoides and Patagonotothen species from the Falkland Islands, minimal in Marion Island Paranotothenia magellanica and Lepidonotothen squamifrons from the South Sandwich and Bouvet islands, to considerable genotype in the Falkland Islands Champsocephalus esox and Marion Island Harpagifer georgianus. All low Antarctic notothenioid species examined show substantial AFGP trait. Mapping of the AFGP trait status onto ND2 phylogenetic trees of a large sampling of notothenioids revealed that AFGP trait reduction or loss occurred at least three independent times in different lineages.

Target-Templated de novo Design of Macrocyclic D-/L-Peptides: Inhibitors of the PD-1/PD-L1 Interaction

2020 ◽  
Author(s):  
Salvador Guardiola ◽  
Monica Varese ◽  
Xavier Roig ◽  
Jesús Garcia ◽  
Ernest Giralt
Keyword(s):  
Protein Interactions ◽  
Cyclic Peptides ◽  
General Framework ◽  
Large Scale ◽  
De Novo ◽  
Inhibitory Effect ◽  
Original Text ◽  
Protein Protein Interactions ◽  
Retraction Notice ◽  
Pharmaceutical Properties

<p>NOTE: This preprint has been retracted by consensus from all authors. See the retraction notice in place above; the original text can be found under "Version 1", accessible from the version selector above.</p><p><br></p><p>------------------------------------------------------------------------</p><p><br></p><p>Peptides, together with antibodies, are among the most potent biochemical tools to modulate challenging protein-protein interactions. However, current structure-based methods are largely limited to natural peptides and are not suitable for designing target-specific binders with improved pharmaceutical properties, such as macrocyclic peptides. Here we report a general framework that leverages the computational power of Rosetta for large-scale backbone sampling and energy scoring, followed by side-chain composition, to design heterochiral cyclic peptides that bind to a protein surface of interest. To showcase the applicability of our approach, we identified two peptides (PD-<i>i</i>3 and PD-<i>i</i>6) that target PD-1, a key immune checkpoint, and work as protein ligand decoys. A comprehensive biophysical evaluation confirmed their binding mechanism to PD-1 and their inhibitory effect on the PD-1/PD-L1 interaction. Finally, elucidation of their solution structures by NMR served as validation of our <i>de novo </i>design approach. We anticipate that our results will provide a general framework for designing target-specific drug-like peptides.<i></i></p>

A Target-Based Method for Designing Heterochiral Cyclic Peptide Binders: De Novo Inhibitors of the PD-1/PD-L1 Interaction

2020 ◽  
Author(s):  
Salvador Guardiola ◽  
Monica Varese ◽  
Xavier Roig ◽  
Jesús Garcia ◽  
Ernest Giralt
Keyword(s):  
Protein Interactions ◽  
Cyclic Peptides ◽  
General Framework ◽  
Large Scale ◽  
Cyclic Peptide ◽  
De Novo ◽  
Inhibitory Effect ◽  
Original Text ◽  
Retraction Notice ◽  
Pharmaceutical Properties

<p>NOTE: This preprint has been retracted by consensus from all authors. See the retraction notice in place above; the original text can be found under "Version 1", accessible from the version selector above.</p><p><br></p><p>------------------------------------------------------------------------</p><p><br></p><p>Peptides, together with antibodies, are among the most potent biochemical tools to modulate challenging protein-protein interactions. However, current structure-based methods are largely limited to natural peptides and are not suitable for designing target-specific binders with improved pharmaceutical properties, such as macrocyclic peptides. Here we report a general framework that leverages the computational power of Rosetta for large-scale backbone sampling and energy scoring, followed by side-chain composition, to design heterochiral cyclic peptides that bind to a protein surface of interest. To showcase the applicability of our approach, we identified two peptides (PD-<i>i</i>3 and PD-<i>i</i>6) that target PD-1, a key immune checkpoint, and work as protein ligand decoys. A comprehensive biophysical evaluation confirmed their binding mechanism to PD-1 and their inhibitory effect on the PD-1/PD-L1 interaction. Finally, elucidation of their solution structures by NMR served as validation of our <i>de novo </i>design approach. We anticipate that our results will provide a general framework for designing target-specific drug-like peptides.<i></i></p>

Target-Templated de novo Design of Macrocyclic D-/L-Peptides: Inhibitors of the PD-1/PD-L1 Interaction

2020 ◽  
Author(s):  
Salvador Guardiola ◽  
Monica Varese ◽  
Xavier Roig ◽  
Jesús Garcia ◽  
Ernest Giralt
Keyword(s):  
Protein Interactions ◽  
Cyclic Peptides ◽  
General Framework ◽  
Large Scale ◽  
De Novo ◽  
Inhibitory Effect ◽  
Original Text ◽  
Protein Protein Interactions ◽  
Retraction Notice ◽  
Pharmaceutical Properties

<p>NOTE: This preprint has been retracted by consensus from all authors. See the retraction notice in place above; the original text can be found under "Version 1", accessible from the version selector above.</p><p><br></p><p>------------------------------------------------------------------------</p><p><br></p><p>Peptides, together with antibodies, are among the most potent biochemical tools to modulate challenging protein-protein interactions. However, current structure-based methods are largely limited to natural peptides and are not suitable for designing target-specific binders with improved pharmaceutical properties, such as macrocyclic peptides. Here we report a general framework that leverages the computational power of Rosetta for large-scale backbone sampling and energy scoring, followed by side-chain composition, to design heterochiral cyclic peptides that bind to a protein surface of interest. To showcase the applicability of our approach, we identified two peptides (PD-<i>i</i>3 and PD-<i>i</i>6) that target PD-1, a key immune checkpoint, and work as protein ligand decoys. A comprehensive biophysical evaluation confirmed their binding mechanism to PD-1 and their inhibitory effect on the PD-1/PD-L1 interaction. Finally, elucidation of their solution structures by NMR served as validation of our <i>de novo </i>design approach. We anticipate that our results will provide a general framework for designing target-specific drug-like peptides.<i></i></p>

scholarly journals Cultural Diplomacy and Europe's Twenty Years’ Crisis, 1919–1939: Introduction

2021 ◽  
pp. 1-15
Author(s):  
Benjamin G. Martin ◽  
Elisabeth Piller
Keyword(s):  
Large Scale ◽  
Cultural Diplomacy ◽  
Good Reason ◽  
Political Leaders ◽  
Distinctive Features ◽  
The Arts ◽  
International Exposition ◽  
German Nation ◽  
Iconic Image ◽  
Industrial Designers

Photographs of the German and Soviet pavilions facing off at the Paris International Exposition in 1937 offer an iconic image of the interwar period, and with good reason. This image captures the interwar period's great conflict of ideologies, the international interconnectedness of the age and the aestheticisation of political and ideological conflict in the age of mass media and mass spectacle. [Figure 1] Last but not least, it captures the importance in the 1930s of what we now call cultural diplomacy. Both pavilions – Germany's, in Albert Speer's neo-classical tower bloc crowned with a giant swastika, and the Soviet Union's, housed in Boris Iofan's forward-thrusting structure topped by Vera Mukhina's monumental sculptural group – represented the outcome of a large-scale collaboration between political leaders and architects, artists, intellectuals and graphic and industrial designers seeking to present their country to foreign visitors in a manner designed to advance the country's interests in the international arena. Each pavilion, that is, made an outreach that was diplomatic – in the sense that it sought to mediate between distinct polities – using means that were cultural – in the sense that they deployed refined aesthetic practices (like the arts and architecture) and in the sense that they highlighted the distinctive features, or ‘culture’, of a particular group (like the German nation or the Soviet state).

Abstract 17081: End Stage Mitochondrial Cardiomyopathy And Heart Transplantation Due To Pathogenic Biallelic C1QBP Variants

Circulation ◽  
2021 ◽  
Vol 144 (Suppl_2) ◽  
Author(s):  
Nicholas S Wilcox ◽  
Stuart Prenner ◽  
Marisa Cevasco ◽  
Courtney Condit ◽  
Amy Goldstein ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Heart Transplantation ◽  
Genome Sequencing ◽  
Large Scale ◽  
De Novo ◽  
Late Onset ◽  
Genetic Disorder ◽  
Disease Onset ◽  
Serum Lactate ◽  
Metabolic Decompensation

Case Presentation: A 29-year-old male with LVH diagnosed in childhood was admitted with acute HF. TTE showed LVEF 5-10% and LV thrombi for which he was anticoagulated. He received inappropriate ICD shocks due to T wave oversensing, leading to cardiogenic shock requiring VA-ECMO support. Serum lactate peaked at 17 mmol/L due to cardiac and metabolic decompensation. He underwent heart transplantation (HT) on hospital day (HD) 8 and tolerated standard immunosuppression. First endomyocardial biopsy showed acute cellular rejection requiring pulse steroids. He was discharged on HD 33. Trio whole exome and mitochondrial genome sequencing revealed biallelic variants in complement component 1Q subcomponent-binding protein ( C1QBP ), due to a maternally inherited likely pathogenic variant c.612C>G (p.F204L in exon 5) and an apparently de novo deletion of 17p13.2, spanning exons 4-6 of C1QBP and exon 6 of the RPAIN gene. Mitochondrial genome sequencing of the explanted heart revealed multiple large-scale mitochondrial DNA deletions at 33% heteroplasmy. Discussion: C1QBP variants are associated with mitochondrial and multi-organ dysfunction. Only 12 patients exhibiting biallelic C1QBP variants are reported. Four died in the peripartum period due to fetal hydrops or HF; 5 exhibited early-onset cardiomyopathy (CM); 3 others had late-onset ophthalmoplegia without CM. The p.F204L variant has been reported in 1 patient with compound C1QBP p.F204L/p.C186S heterozygosity who died from hydrops fetalis and a second with p.F204L homozygosity with late-onset ophthalmoplegia and skeletal myopathy without CM. Differences in the size, heteroplasmy, and tissue distribution of mitochondrial genome secondary deletions may explain variability in disease onset and progression. We present the first patient with biallelic pathogenic C1QBP gene variants with mitochondrial CM to undergo HT and highlight the diagnosis and management of an exceptionally uncommon genetic disorder.

A comparative analysis of “Hutsulka” in the performing interpretations by two violinists representing the tradition of the Kosmach-Brusturiv areal

Ethnomusic ◽  
2018 ◽  
Vol 14 (1) ◽  
pp. 142-177
Author(s):  
Jarema Pavliv ◽  
Keyword(s):  
Comparative Analysis ◽  
Large Scale ◽  
Mobile Elements ◽  
Strategic Performance ◽  
Distinctive Features ◽  
Eastern Carpathians ◽  
Linear Movement ◽  
Melodic Line ◽  
Individual Interpretation ◽  
Formal Features

In the offered article, a comparative analysis of two performing versions of the wedding ceremonial dance “Hutsulka”, dominant in the Eastern Carpathians region of Ukraine has been made, with outstanding violinists-capellists, which, based on traditions and their own virtuoso style, developed this dance genre due to the accumulation of stable and mobile elements of melo-, rhythm- and form-making, as well as the establishment of aesthetics of regional styles. The material for the study was the audio version of the “Hutsulka” recorded on the basis of the performance of two violinists representing the region of Kosmach- Brusturiv villages tradition – Kyrylo Lyndiuk (“Vityshyn”, 1929–2003) (recorded by prof. Bogdan Lukaniuk in 1991) and Ivan Sokoliuk (born in 1944; Musician's own recording of 2017) – and transcribed by the author of the article. The performance of “Hutsulka” by each violinist is characteristic of common and distinctive features concerning the formation of the variative composition, the thematic material (respectively, 29 and 43 themes of kolomyika, kozachok and voloshka bases), tonality and rhythmic structuring, individual interpretation of ornamentation, which is collectively connected with artistic orientation on certain artistic and performing directions, presented by iconic musicians-predecessors. The formal features of the Hutsulka composition depends on scenery where it is performed (1); the tonality outline determined by established regional tradition (2), and rhythmic outline, by the overall style, varyation technics, updating and ornamentation of rhythmic formulas, characteristic of the personal manner and style of the performer (3). Ornamentation, as the essence of the performing style of any Hutsul musician, in K. “Vityshyn” is characterized by intense interweaving of short melismatic legal groups and non-legal figurations within melodic line and texture. I. Sokoliuk 166 enriches the linear movement with prolonged melismatic groups and rhythm- intonational and figurational turns that decorate it and amplify the expression of dance overall sonority. In performing aesthetics of K. Lyndiuk prevails an acute articulation of melodic expressiveness with accented and often pointed rhythmic patterns that provides representative-temperamental virtuosity. For strategic performance aesthetics of I. Sokoliuk, rich in virtuosic expressiveness, is characterized by choral and transparent ringing articulation in the context of “stratum”-development creation of the whole large-scale virtuoso composition. Each version reveals individual compositional, improvised, techno-performing, emotional as well as aesthetic mind of their creators. All these qualities, formed by both musicians in a single tradition and expressed in related kolomyika and kozachok-voloshka tunes, present the decision of developmental, composite, rhythmic, intonational, articulation, tempo and many other aspects of style, characteristic of folk violinists – soloists and capellists, inherent to each of them, in their performing manner, evident in “Hutsulka” rendering.

scholarly journals Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Tianyun Wang ◽  
◽  
Kendra Hoekzema ◽  
Davide Vecchio ◽  
Huidan Wu ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Large Scale ◽  
De Novo ◽  
Targeted Sequencing ◽  
Published Data ◽  
De Novo Mutations ◽  
Risk Genes ◽  
Mutation Burden ◽  
Number Of Patients ◽  
Significant Burden

Abstract Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

scholarly journals Phorbol ester induces the biosynthesis of glycosylated and nonglycosylated plasminogen activator inhibitor 2 in high excess over urokinase-type plasminogen activator in human U-937 lymphoma cells.

1987 ◽  
Vol 104 (3) ◽  
pp. 705-712 ◽  
Author(s):  
C Genton ◽  
E K Kruithof ◽  
W D Schleuning
Keyword(s):  
Plasminogen Activator ◽  
Phorbol Ester ◽  
Large Scale ◽  
De Novo ◽  
Plasminogen Activator Inhibitor ◽  
Conditioned Media ◽  
Cell Extracts ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Activator Inhibitor

The tumor-promoting phorbol ester PMA induces changes in the histiocytic human lymphoma cell line U-937 akin to cellular differentiation (Ralph, P., N. Williams, M. A. S. Moore, and P. B. Litcofsky, 1982, Cell. Immunol., 71:215-223) and concomitantly stimulates the biosynthesis of plasminogen activator inhibitor 2 (PAI 2) and of urokinase-type plasminogen activator (u-PA). PAI 2 is found in a nonglycosylated intracellular and a glycosylated secreted form. The former appears to be identical to PAI 2 previously purified from placental extracts and large-scale U-937 cell cultures. The sixfold increase of PAI 2 antigen measured 24 h after PMA treatment in cell extracts and conditioned media is accompanied by an equal increase of active PAI 2 mRNA, whereas the 6 to 13-fold increase of u-PA antigen in the same samples is associated with only a 1.5-fold mRNA increase. The increase of PAI 2, but not of u-PA, biosynthesis requires transcription. A 50-fold molar excess of PAI 2 over u-PA is found in both extracts and conditioned media of PMA-treated cells. PAI 2 represents at least 0.3% of total de novo synthesized protein 24 h after induction with PMA. Thus, PAI 2, but not u-PA, is an abundant product of this precursor analogue of the mononuclear phagocyte lineage, and might represent a new marker for monocyte/macrophage differentiation.

scholarly journals Accurate long-read de novo assembly evaluation with Inspector

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yu Chen ◽  
Yixin Zhang ◽  
Amy Y. Wang ◽  
Min Gao ◽  
Zechen Chong
Keyword(s):  
Genome Assembly ◽  
De Novo Assembly ◽  
In Silico ◽  
Large Scale ◽  
De Novo ◽  
Small Scale ◽  
De Novo Genome Assembly ◽  
Consensus Sequences ◽  
Assembly Evaluation ◽  
Long Read

AbstractLong-read de novo genome assembly continues to advance rapidly. However, there is a lack of effective tools to accurately evaluate the assembly results, especially for structural errors. We present Inspector, a reference-free long-read de novo assembly evaluator which faithfully reports types of errors and their precise locations. Notably, Inspector can correct the assembly errors based on consensus sequences derived from raw reads covering erroneous regions. Based on in silico and long-read assembly results from multiple long-read data and assemblers, we demonstrate that in addition to providing generic metrics, Inspector can accurately identify both large-scale and small-scale assembly errors.

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