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Multi-cohort proteogenomic analyses reveal genetic effects across the proteome and diseasome.

Understanding the genetic regulation of circulating protein levels can provide new insights into disease mechanisms. Here, we present the la … enotypic insights. We identify proteins as candidates for drug targets and engagement (e.g., plasma furin and cardiovascular diseases) by comparing cis-based genetic evidence with protein-disease associations. Systematic triangulation of trans-protein QTLs (pQTLs) with genetic and protein associations across many diseases highlights potential drug repur …

Biallelic variants of SEMA3F are associated with nonsyndromic hearing loss.

It is crucial to manage hearing loss and its associated public health impacts. In this study, we aimed to understand the role of Sema3f in t … th congenital onset. In vitro analysis revealed that the identified missense variants decreased the furin-mediated processing of SEMA3F and abolished the cellular abilities of SEMA3F, which collapsed the filamentous actin cytoskeleton in human umbilical vein-derived endothelial cells. Our data suggest that SEMA3F is essential for normal hearing and is a …

Development of SARS-CoV-2 as a viral vector: A novel intranasal bivalent vaccine for SARS-CoV-2 and RSV.

Negative-sense RNA viruses have been widely used as viral vectors for vaccine delivery. However, little is known about coronaviruses as vectors for delivering vaccines. Here, we have developed safe SARS-CoV-2 Omicron JN.1-based live attenuated vaccine candidates by combining a mutation (D130A) in the viral nsp16 protein, deletion of the furin cleavage site (dFCS) in the spike protein, deletion of accessory proteins, and/or modification of the transcription regulatory sequences (mTRS). Subsequently, using rJN.1, rJN.1-D130A-dFCS, and rJN.1-mTRS-D130A-dFCS as the backbones, we generated three re…

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein.

The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SA…

Cell-penetrating peptide-mediated cell entry of H5N1 highly pathogenic avian influenza virus.

H5N1 highly pathogenic avian influenza virus (HPAIV) poses a huge threat to public health and the global economy. These viruses cause system … sialic acid-deficient cells, and virus internalisation was facilitated by cleavage with recombinant furin. Thus, our findings demonstrate that the HA314-46 motif exhibits cell-penetrating activity through a sialic acid-independent cell entry mechanism.

Генетически модифицированные, живые, смягченные вакцины защищают нечеловеческие приматы от аэрозольного вызова с вирулентным штаммом IE вируса энцефалита венесуэльского энцефалита.

Два живых штамма вируса энцефалита (VEE), IE1150K и V3526, которые были использованы для определения того, могут ли они обеспечить защиту от аэрозольного вызова вирусом VEE разновидности IE (VEV-IE). Эти вирусы были спасены из клонов CDNA полной длины 68U201 (вид VEV-IE) и из осла Тринидада (вид VEV-IA/B), соответственно, и оба из них имеют мутации фуриновой декольте и реанимационную мутации второго участка. Обе вакцины привели к нейтрализации антител к вирусам гомологической разновидности, но не к вирусам гетерологической разновидности. Через восемь недель после вакцинации макаки подверглись

Совпадение в аннотации оригинала
Two live, attenuated strains of Venezuelan equine encephalitis virus (VEE), IE1150K and V3526, were administered to macaques to determine if … of 68U201 (VEEV-IE variety) and Trinidad donkey (VEEV-IA/B variety), respectively, and both have a furin cleavage site deletion mutation and a second-site resuscitating mutation. Both vaccines elicited neutralizing antibodies to viruses of the homologous variety but not to viruses of the heterologous variety. Eight weeks after vaccination, the macaques …

Gene editing of pigs to control influenza A virus infections.

Proteolytic activation of the hemagglutinin (HA) glycoprotein by host cellular proteases is pivotal for influenza A virus (IAV) infectivity. Highly pathogenic avian influenza viruses possess the multibasic cleavage site of the HA which is cleaved by ubiquitous proteases, such as furin; in contrast, the monobasic HA motif is recognized and activated by trypsin-like proteases, such as the transmembrane serine protease 2 (TMPRSS2). Here, we aimed to determine the effects of TMPRSS2 on the replication of pandemic H1N1 and H3N2 subtype IAVs in the natural host, the pig. The use of the CRISPR/Cas 9 …

Mind the feline coronavirus: Comparison with SARS-CoV-2.

Both feline coronavirus (FCoV) and SARS-CoV-2 are coronaviruses that infect cats and humans, respectively. However, cats have been shown to … d to the main characteristics of the genome, receptor usage, and RBD of spike proteins with similar furin cleavage sites. In particular, the affinity of the conserved feline angiotensin-converting enzyme 2 (fACE2) receptor to the RBD of SARS-CoV-2 suggests that cats are susceptible to SARS-CoV-2. In addition, cross-species of coronaviruses between cats …

Asprosin, a C-Terminal Cleavage Product of Fibrillin 1 Encoded by the FBN1 Gene, in Health and Disease.

BACKGROUND: Asprosin is a novel fasting-induced, glucogenic, and orexigenic protein hormone that is discovered with the help of genetic studies in patients with neonatal progeroid syndrome. Asprosin is encoded by the penultimate 2 exons (65 and 66) of the fibrillin 1 (FBN1) gene. Profibrillin 1 is the unprocessed protein product of FBN1 and undergoes a proteolytic cleavage by furin enzyme to produce mature fibrillin 1 and asprosin. The main organ responsible for the asprosin production seems to be white adipose tissue. SUMMARY: Asprosin promotes hepatic glucose release in the liver and appeti…

Structural basis for the kexin-like serine protease from Aeromonas sobria as sepsis-causing factor.

The anaerobic bacterium Aeromonas sobria is known to cause potentially lethal septic shock. We recently proposed that A. sobria serine protease (ASP) is a sepsis-related factor that induces vascular leakage, reductions in blood pressure via kinin release, and clotting via activation of prothrombin. ASP preferentially cleaves peptide bonds that follow dibasic amino acid residues, as do Kex2 (Saccharomyces cerevisiae serine protease) and furin, which are representative kexin family proteases. Here, we revealed the crystal structure of ASP at 1.65 A resolution using the multiple isomorphous repla…

Latent cytokines: development of novel cleavage sites and kinetic analysis of their differential sensitivity to MMP-1 and MMP-3.

We have engineered a latent mouse interferon beta (mIFNbeta) using the latency associated peptide (LAP) of transforming growth factor beta1 … as the best substrate for both enzymes. The introduction of a hydrophilic sequence derived from the furin cleavage site of the anthrax toxin protective antigen increased the sensitivity to MMP-3 to up to 29-fold. These data suggest that this strategy could be useful for improving the effectiveness of the delivery and targeting of protein therapeutics.

Collagen XVII is destabilized by a glycine substitution mutation in the cell adhesion domain Col15.

Collagen XVII is a hemidesmosomal transmembrane molecule important for epithelial adhesion in the skin. It exists in two forms, as a full-length protein and as a soluble ectodomain that is shed from the keratinocyte surface by furin-mediated proteolysis. To obtain information on the conformation and the functions of this unusual collagen, its largest collagenous domain, Col15, was expressed in a eukaryotic episomal expression system and purified by DEAE and fast protein liquid- Mono S chromatography. The protein was triple-helical (T(m) of 26.5 degrees C) when produced in cultures containing a…

Limited potential for mosquito transmission of genetically engineered, live-attenuated Venezuelan equine encephalitis virus vaccine candidates.

In an attempt to improve the current live-attenuated vaccine (TC-83) for Venezuelan equine encephalitis (VEE), specific mutations associated … natural vector of epizootic VEE virus. Two vaccine candidates, one containing a deletion of the PE2 furin cleavage site, the other a combination of three separate point mutations in the E2 glycoprotein, replicated in mosquitoes and were transmitted to hamsters significantly less efficiently than was either parental (wild type) VEE virus or TC-83 virus. …

Ubiquitin ligase ITCH regulates life cycle of SARS-CoV-2 virus.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection poses a major threat to public health, and understanding the mechanis … heir autophagosome-dependent secretion. Additionally, ITCH disrupts the trafficking of the protease furin and the maturation of cathepsin L, thereby suppressing their activities in cleaving and destabilizing the viral spike protein. Furthermore, ITCH exhibits robust activation during the SARS-CoV-2 replication stage, and SARS-CoV-2 replication is signif …

Gene editing of pigs to control influenza A virus infections.

Proteolytic activation of the haemagglutinin (HA) glycoprotein by host cellular proteases is pivotal for influenza A virus (IAV) infectivity. Highly pathogenic avian influenza viruses possess the multibasic cleavage site of the HA which is cleaved by ubiquitous proteases, such as furin; in contrast, the monobasic HA motif is recognized and activated by trypsin-like proteases, such as the transmembrane serine protease 2 (TMPRSS2). Here, we aimed to determine the effects of TMPRSS2 on the replication of pandemic H1N1 and H3N2 subtype IAVs in the natural host, the pig. The use of the CRISPR/Cas 9…

Viral and Host Attributes Underlying the Origins of Zoonotic Coronaviruses in Bats.

With a presumed origin in bats, the COVID-19 pandemic has been a major source of morbidity and mortality in the hu- man population, and the … g domain, a unique aspect of SARS-CoV-2 as compared with its closest relatives is the presence of a furin cleavage site in the S1-S2 region of the spike protein. Proteolytic activation is likely an important feature that allows SARS-CoV-2-and other coronaviruses-to overcome the species barriers and thus cause human disease. The diversity of bat species …

COVID-19 and human spermatozoa-Potential risks for infertility and sexual transmission?

As COVID-19 infections wreak havoc across the globe, attention has rightly been focused on the vital organ systems (lung, kidney and heart) … e integration, given the additional presence of a range of proteases (TMPRSS2, TMPRSS11B, TMPRSS12, furin) capable of promoting viral fusion. This article reviews the roles played by these various cellular constituents in maintaining the vitality of human spermatozoa and their competence for fertilization. The reproductive consequences of a viral attack …

Tumor Targeting and Drug Delivery by Anthrax Toxin.

Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated and to deliver the enzymatic moieties lethal factor and edema factor to the cytosol of cells. Alteration of the protease cleavage site allows the activation of the toxin selectively in response to the presence of tumor-associated proteases. This initial idea of re-targeting anthrax toxin to tumor cells was further elaborated i…

Proteomics-based identification of plasma proteins and their association with the host-pathogen interaction in chronic typhoid carriers.

BACKGROUND: Current diagnostic tests are inadequate to detect typhoid cases, as well as the chronic carrier state, the sole reservoir of Sal … ic typhoid carriers. RESULTS: Results showed the upregulation of proprotein convertase subtilisin, furin, haptoglobin, and albumin in the plasma of chronic typhoid carriers. The elevation in mRNA expression of four differentially expressed proteins confirms the changes at the transcriptional level. Further, the increase in albumin and haptoglobin in ch …

Expression of cholera toxin B-lumbrokinase fusion protein in Pichia pastoris--the use of transmucosal carriers in the delivery of therapeutic proteins to protect rats against thrombosis.

Cholera toxin B-subunit (CTB) has been widely used to facilitate antigen delivery by serving as an effective mucosal carrier molecule for the induction of oral tolerance. However, whether CTB can be used as a transmucosal carrier in the delivery of not only vaccines but also therapeutic proteins has not been widely studied. Thus, we investigate here the concept of receptor-mediated oral delivery of lumbrokinase (LK) proteins which is an important fibrinolytic enzyme derived from earthworm. CTB and LK, separated by a furin cleavage site, was expressed via Pichia pastoris. The activity and prope…