scholarly journals The Importance of N186 in the Alpha-1-Antitrypsin Shutter Region Is Revealed by the Novel Bologna Deficiency Variant

2021 ◽  
Vol 22 (11) ◽  
pp. 5668
Author(s):  
Riccardo Ronzoni ◽  
Ilaria Ferrarotti ◽  
Emanuela D’Acunto ◽  
Alice M. Balderacchi ◽  
Stefania Ottaviani ◽  
...  
Keyword(s):  
Rare Variants ◽  
Culture Media ◽  
The Novel ◽  
Domain Swap ◽  
Cellular Models ◽  
New Variant ◽  
Alpha 1 Antitrypsin ◽  
Structural Mechanisms ◽  
Insoluble Polymers

Alpha-1-antitrypsin (AAT) deficiency causes pulmonary disease due to decreased levels of circulating AAT and consequently unbalanced protease activity in the lungs. Deposition of specific AAT variants, such as the common Z AAT, within hepatocytes may also result in liver disease. These deposits are comprised of ordered polymers of AAT formed by an inter-molecular domain swap. The discovery and characterization of rare variants of AAT and other serpins have historically played a crucial role in the dissection of the structural mechanisms leading to AAT polymer formation. Here, we report a severely deficient shutter region variant, Bologna AAT (N186Y), which was identified in five unrelated subjects with different geographical origins. We characterized the new variant by expression in cellular models in comparison with known polymerogenic AAT variants. Bologna AAT showed secretion deficiency and intracellular accumulation as detergent-insoluble polymers. Extracellular polymers were detected in both the culture media of cells expressing Bologna AAT and in the plasma of a patient homozygous for this variant. Structural modelling revealed that the mutation disrupts the hydrogen bonding network in the AAT shutter region. These data support a crucial coordinating role for asparagine 186 and the importance of this network in promoting formation of the native structure.

scholarly journals Molecular and biochemical insights into the in vivo evolution of AmpC-mediated resistance to ceftolozane/tazobactam during treatment of an MDR Pseudomonas aeruginosa infection

2020 ◽  
Vol 75 (11) ◽  
pp. 3209-3217 ◽  
Author(s):  
Jorge Arca-Suárez ◽  
Juan Carlos Vázquez-Ucha ◽  
Pablo Arturo Fraile-Ribot ◽  
Emilio Lence ◽  
Gabriel Cabot ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Conformational Changes ◽  
Catalytic Efficiency ◽  
The Novel ◽  
Development Of Resistance ◽  
New Variant ◽  
Ic50 Values ◽  
Dynamics Simulations

Abstract Background Pseudomonas aeruginosa may develop resistance to novel cephalosporin/β-lactamase inhibitor combinations during therapy through the acquisition of structural mutations in AmpC. Objectives To describe the molecular and biochemical mechanisms involved in the development of resistance to ceftolozane/tazobactam in vivo through the selection and overproduction of a novel AmpC variant, designated PDC-315. Methods Paired susceptible/resistant isolates obtained before and during ceftolozane/tazobactam treatment were evaluated. MICs were determined by broth microdilution. Mutational changes were investigated through WGS. Characterization of the novel PDC-315 variant was performed through genotypic and biochemical studies. The effects at the molecular level of the Asp245Asn change were analysed by molecular dynamics simulations using Amber. Results WGS identified mutations leading to modification (Asp245Asn) and overproduction of AmpC. Susceptibility testing revealed that PAOΔC producing PDC-315 displayed increased MICs of ceftolozane/tazobactam, decreased MICs of piperacillin/tazobactam and imipenem and similar susceptibility to ceftazidime/avibactam compared with WT PDCs. The catalytic efficiency of PDC-315 for ceftolozane was 10-fold higher in relation to the WT PDCs, but 3.5- and 5-fold lower for piperacillin and imipenem. IC50 values indicated strong inhibition of PDC-315 by avibactam, but resistance to cloxacillin inhibition. Analysis at the atomic level explained that the particular behaviour of PDC-315 is linked to conformational changes in the H10 helix that favour the approximation of key catalytic residues to the active site. Conclusions We deciphered the precise mechanisms that led to the in vivo emergence of resistance to ceftolozane/tazobactam in P. aeruginosa through the selection of the novel PDC-315 enzyme. The characterization of this new variant expands our knowledge about AmpC-mediated resistance to cephalosporin/β-lactamase inhibitors in P. aeruginosa.

Characterization of the Serum a1-Antitripsine Level in Primary Spontaneous Pneumotorax Patients

2018 ◽  
Vol 69 (9) ◽  
pp. 2591-2593
Author(s):  
Cristina Grigorescu ◽  
Liviu Ciprian Gavril ◽  
Laura Gavril ◽  
Tiberiu Lunguleac ◽  
Bogdan Mihnea Ciuntu ◽  
...  
Keyword(s):  
Serum Level ◽  
Pulmonary Emphysema ◽  
Spontaneous Pneumothorax ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Determining Factor

Diagnosis of primary or idiopathic spontaneous pneumothorax is one of exclusion, and in fact defines an entity that may have a difficult or impossible cause to be highlighted by current means, we consider it appropriate to study these etiopathogenic aspects. There is a definite association between alpha-1 antitrypsin deficiency and pulmonary emphysema and indirect spontaneous pneumothorax secondary to an emphysematous pulmonary lesion. Dose of alpha-1 antitrypsin is an immunoturbinimetric method for in vitro determination of alpha-1 antitrypsin in human serum and plasma. This product is calibrated to be used for the Daytona RX analyzer. The serum level of alpha-1-antitrypsin is not a determining factor in the postoperative evolution characterized by the interval until air loss disappears, but certainly exerts some influence, the exact level of which remains to be determined.

Characterization of the novel HLA‐C *07:944 allele by next‐generation sequencing

HLA ◽  
2021 ◽  
Author(s):  
Maria Loginova ◽  
Olga Makhova ◽  
Daria Smirnova ◽  
Igor Paramonov ◽  
Maksim Zarubin
Keyword(s):  
Next Generation Sequencing ◽  
The Novel ◽  
Next Generation ◽  
Generation Sequencing

Characterization of the novel HLA‐B *51:296 allele by next‐generation sequencing

HLA ◽  
2020 ◽  
Author(s):  
Steve Genebrier ◽  
Vincent Elsermans ◽  
Emeric Texeraud ◽  
Gerald Bertrand ◽  
Virginie Renac
Keyword(s):  
Next Generation Sequencing ◽  
The Novel ◽  
Next Generation ◽  
Generation Sequencing

Characterization of the novel HLA‐DRB1*11:282 allele by sequencing‐based typing

HLA ◽  
2021 ◽  
Author(s):  
Marine Cargou ◽  
Vincent Elsermans ◽  
Isabelle Top ◽  
Laura Blouin ◽  
Jonathan Visentin
Keyword(s):  
The Novel

scholarly journals Isolation and Characterization of Salmonella Jumbo-Phage pSal-SNUABM-04

Viruses ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 27
Author(s):  
Jun Kwon ◽  
Sang Guen Kim ◽  
Hyoun Joong Kim ◽  
Sib Sankar Giri ◽  
Sang Wha Kim ◽  
...  
Keyword(s):  
Morphological Traits ◽  
Open Reading Frames ◽  
Genome Comparison ◽  
The Novel ◽  
Promising Alternative ◽  
Isolation And Characterization ◽  
Global Issue ◽  
Reading Frames ◽  
Predicted Function

The increasing emergence of antimicrobial resistance has become a global issue. Therefore, many researchers have attempted to develop alternative antibiotics. One promising alternative is bacteriophage. In this study, we focused on a jumbo-phage infecting Salmonella isolated from exotic pet markets. Using a Salmonella strain isolated from reptiles as a host, we isolated and characterized the novel jumbo-bacteriophage pSal-SNUABM-04. This phage was investigated in terms of its morphology, host infectivity, growth and lysis kinetics, and genome. The phage was classified as Myoviridae based on its morphological traits and showed a comparatively wide host range. The lysis efficacy test showed that the phage can inhibit bacterial growth in the planktonic state. Genetic analysis revealed that the phage possesses a 239,626-base pair genome with 280 putative open reading frames, 76 of which have a predicted function and 195 of which have none. By genome comparison with other jumbo phages, the phage was designated as a novel member of Machinavirus composed of Erwnina phages.

Characterization of the novel HLA‐DQA1 *05:19 allele by next‐generation sequencing

HLA ◽  
2021 ◽  
Author(s):  
Steve Genebrier ◽  
Paul Rouzaire ◽  
Emeric Texeraud ◽  
Gerald Bertrand ◽  
Virginie Renac
Keyword(s):  
Next Generation Sequencing ◽  
The Novel ◽  
Next Generation ◽  
Hla Dqa1 ◽  
Generation Sequencing

scholarly journals Isolation and characterization of the new SARS-CoV-2 variant in travellers from the United Kingdom to India: VUI-202012/01 of the B.1.1.7 lineage

2021 ◽  
Vol 28 (2) ◽  
Author(s):  
Pragya D Yadav ◽  
Dimpal A Nyayanit ◽  
Rima R Sahay ◽  
Prasad Sarkale ◽  
Jayshri Pethani ◽  
...  
Keyword(s):  
United Kingdom ◽  
Severe Acute Respiratory Syndrome ◽  
Surveillance System ◽  
The United Kingdom ◽  
Isolation And Characterization ◽  
New Variant ◽  
The Uk ◽  
Local Transmission

We have isolated the new severe acute respiratory syndrome coronavirus-2 variant of concern 202 012/01 from the positive coronavirus disease 2019 cases that travelled from the UK to India in the month of December 2020. This emphasizes the need for the strengthened surveillance system to limit the local transmission of this new variant.

scholarly journals HINT1 neuropathy in Norway: clinical, genetic and functional profiling

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Silvia Amor-Barris ◽  
Helle Høyer ◽  
Lin V. Brauteset ◽  
Els De Vriendt ◽  
Linda Strand ◽  
...  
Keyword(s):  
Axonal Neuropathy ◽  
Functional Characterization ◽  
Treatment Strategies ◽  
Central Nervous System Involvement ◽  
Sensory Neuropathy ◽  
Muscle Stiffness ◽  
Compound Heterozygous ◽  
Clinical Genetic ◽  
Cellular Models ◽  
New Variant

Abstract Background Autosomal recessive axonal neuropathy with neuromyotonia has been linked to loss of functional HINT1. The disease is particularly prevalent in Central and South-East Europe, Turkey and Russia due to the high carrier frequency of the c.110G > C (p.Arg37Pro) founder variant. Results In a cohort of 748 Norwegian patients with suspected peripheral neuropathy, we identified two seemingly unrelated individuals, compound heterozygous for a new variant (c.284G > A, p.Arg95Gln) and the most common pathogenic founder variant (c.110G > C, p.Arg37Pro) in the HINT1 gene. Probands presented with motor greater than sensory neuropathy of various onset, accompanied by muscle stiffness and cramps in the limbs. Furthermore, they displayed non-classical symptoms, including pain in the extremities and signs of central nervous system involvement. Haplotype analysis in both patients revealed a common chromosomal background for p.Arg95Gln; moreover, the variant was identified in Swedish carriers. Functional characterization in HINT1-knockout and patient-derived cellular models, and in HNT1-knockout yeast, suggested that the new variant is deleterious for the function of HINT1 and provided mechanistic insights allowing patient stratification for future treatment strategies. Conclusion Our findings broaden the genetic epidemiology of HINT1-neuropathy and have implications for molecular diagnostics of inherited peripheral neuropathies in Scandinavia.

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