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BioRxiv : the Preprint Server For... May 2024H5 influenza is considered a potential pandemic threat. Recently, H5 viruses belonging to clade 2.3.4.4b have caused large outbreaks in avian and multiple non-human...
H5 influenza is considered a potential pandemic threat. Recently, H5 viruses belonging to clade 2.3.4.4b have caused large outbreaks in avian and multiple non-human mammalian species. Previous studies have identified molecular phenotypes of the viral hemagglutinin (HA) protein that contribute to pandemic potential in humans, including cell entry, receptor preference, HA stability, and reduced neutralization by polyclonal sera. However, prior experimental work has only measured how these phenotypes are affected by a handful of the >10,000 different possible amino-acid mutations to HA. Here we use pseudovirus deep mutational scanning to measure how all mutations to a 2.3.4.4b H5 HA affect each phenotype. We identify mutations that allow HA to better bind α2-6-linked sialic acids, and show that some viruses already carry mutations that stabilize HA. We also measure how all HA mutations affect neutralization by sera from mice and ferrets vaccinated against or infected with 2.3.4.4b H5 viruses. These antigenic maps enable rapid assessment of when new viral strains have acquired mutations that may create mismatches with candidate vaccine strains. Overall, the systematic nature of deep mutational scanning combined with the safety of pseudoviruses enables comprehensive measurements of the phenotypic effects of mutations that can inform real-time interpretation of viral variation observed during surveillance of H5 influenza.
PubMed: 38826368
DOI: 10.1101/2024.05.23.595634 -
Veterinary Immunology and... Jul 2024Influenza A virus (IAV) is a major pathogen in the swine industry. Whole-inactivated virus (WIV) vaccines in swine are highly effective against homologous viruses but...
Influenza A virus (IAV) is a major pathogen in the swine industry. Whole-inactivated virus (WIV) vaccines in swine are highly effective against homologous viruses but provide limited protection to antigenically divergent viruses and may lead to vaccine-associated enhanced respiratory disease (VAERD) after heterologous infection. Although VAERD is reproducible in laboratory studies, clinical diagnosis is challenging, as it would require both knowledge of prior vaccine history and evidence of severe disease by assessment of pathologic lesions at necropsy following infection with a heterologous virus. The objective of this study was to identify potential biomarkers for VAERD for antemortem clinical diagnosis. Naïve pigs were split into two groups, and one group was vaccinated with IAV WIV vaccine. All pigs were then challenged with a heterologous virus to induce VAERD in the vaccinated group and necropsied at 5 days post infection (dpi). Blood was collected on 0, 1, 3, and 5 dpi, and assessed by hematology, plasma chemistry, acute phase proteins, and citrullinated H3 histone (CitH3) assays. Additionally, cytokine and CitH3 levels were assessed in bronchoalveolar lavage fluid (BALF) collected at necropsy. Compared to nonvaccinated challenged pigs, blood collected from vaccinated and challenged (V/C) pigs with VAERD had elevated white blood cells and neutrophils, elevated C-reactive protein and haptoglobin acute phase proteins, and elevated CitH3. In BALF, the proinflammatory cytokine IL-8 and CitH3 were elevated in V/C pigs. In conclusion, a profile of elevated white blood cells and neutrophils, elevated C-reactive protein and haptoglobin, and elevated CitH3 may be relevant for a clinical antemortem IAV VAERD diagnosis.
Topics: Animals; Swine; Orthomyxoviridae Infections; Swine Diseases; Influenza Vaccines; Biomarkers; Influenza A virus; Bronchoalveolar Lavage Fluid; Cytokines; Vaccines, Inactivated
PubMed: 38815504
DOI: 10.1016/j.vetimm.2024.110787 -
The Primary Care Companion For CNS... May 2024
Topics: Humans; Creutzfeldt-Jakob Syndrome
PubMed: 38815266
DOI: 10.4088/PCC.23cr03637 -
Biochemical Society Transactions Jun 2024The dysfunction of many RNA-binding proteins (RBPs) that are heavily disordered, including TDP-43 and FUS, are implicated in amyotrophic lateral sclerosis and... (Review)
Review
The dysfunction of many RNA-binding proteins (RBPs) that are heavily disordered, including TDP-43 and FUS, are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). These proteins serve many important roles in the cell, and their capacity to form biomolecular condensates (BMCs) is key to their function, but also a vulnerability that can lead to misregulation and disease. Matrin-3 (MATR3) is an intrinsically disordered RBP implicated both genetically and pathologically in ALS/FTD, though it is relatively understudied as compared with TDP-43 and FUS. In addition to binding RNA, MATR3 also binds DNA and is implicated in many cellular processes including the DNA damage response, transcription, splicing, and cell differentiation. It is unclear if MATR3 localizes to BMCs under physiological conditions, which is brought further into question due to its lack of a prion-like domain. Here, we review recent studies regarding MATR3 and its roles in numerous physiological processes, as well as its implication in a range of diseases.
Topics: Humans; RNA-Binding Proteins; Amyotrophic Lateral Sclerosis; Nuclear Matrix-Associated Proteins; Frontotemporal Dementia; DNA-Binding Proteins; Animals; DNA Damage; RNA-Binding Protein FUS
PubMed: 38813817
DOI: 10.1042/BST20220585 -
Frontiers in Veterinary Science 2024Prion diseases in mammals are caused by the structural conversion of the natural prion protein (PrP) to a pathogenic isoform, the "scrapie form of prion protein (PrP)."...
BACKGROUND
Prion diseases in mammals are caused by the structural conversion of the natural prion protein (PrP) to a pathogenic isoform, the "scrapie form of prion protein (PrP)." Several studies reported that the shadow of prion protein (Sho), encoded by the shadow of prion protein gene (), is involved in prion disease development by accelerating the conformational conversion of PrP to PrP. Until now, genetic polymorphisms of the gene and the protein structure of Sho related to fragility to prion disease have not been investigated in pheasants, which are a species of poultry.
METHODS
Here, we identified the gene sequence by polymerase chain reaction (PCR) and compared the gene and Sho protein sequences among various prion disease-susceptible and -resistant species to identify the distinctive genetic features of pheasant Sho using Clustal Omega. In addition, we investigated genetic polymorphisms of the gene in pheasants and analyzed genotype, allele, and haplotype frequencies, as well as linkage disequilibrium among the genetic polymorphisms. Furthermore, we used programs, namely Mutpred2, MUpro and AMYCO, to investigate the effect of non-synonymous single nucleotide polymorphisms (SNPs). Finally, the predicted secondary and tertiary structures of Sho proteins from various species were analyzed by Alphafold2.
RESULTS
In the present study, we reported pheasant gene sequences for the first time and identified a total of 14 novel SNPs, including 7 non-synonymous and 4 synonymous SNPs. In addition, the pheasant Sho protein sequence showed 100% identity with the chicken Sho protein sequence. Furthermore, amino acid substitutions were predicted to affect the hydrogen bond distribution in the 3D structure of the pheasant Sho protein.
CONCLUSION
To the best of our knowledge, this is the first report of the genetic and structural features of the pheasant gene.
PubMed: 38812560
DOI: 10.3389/fvets.2024.1399548 -
Progress in Molecular Biology and... 2024The scientific community is very interested in protein aggregation because of its involvement in several neurodegenerative diseases and its significance in industry.... (Review)
Review
The scientific community is very interested in protein aggregation because of its involvement in several neurodegenerative diseases and its significance in industry. Remarkably, fibrillar aggregates are utilized naturally for constructing structural scaffolds or creating biological switches and may be intentionally designed to construct versatile nanomaterials. Consequently, there is a significant need to rationalize and predict protein aggregation. Researchers have developed various computational methodologies and algorithms to predict protein aggregation and understand its underlying mechanics. This chapter aims to summarize the significant advancements in computational methods, accessible resources, and prospective developments in the field of in silico research. We assess the existing computational tools for predicting protein aggregation propensities, detecting areas that are prone to sequential and structural aggregation, analyzing the effects of mutations on protein aggregation, or identifying prion-like domains.
Topics: Protein Aggregates; Humans; Proteins; Computational Biology; Algorithms
PubMed: 38811082
DOI: 10.1016/bs.pmbts.2024.03.005 -
Progress in Molecular Biology and... 2024Amyloid fibrils are insoluble proteins with intricate β-sheet structures associated with various human diseases, including Parkinson's, Alzheimer's, and prion diseases.... (Review)
Review
Amyloid fibrils are insoluble proteins with intricate β-sheet structures associated with various human diseases, including Parkinson's, Alzheimer's, and prion diseases. Proteins can form aggregates when their structure is misfolded, resulting in highly organized amyloid fibrils or amorphous aggregates. The formation of protein aggregates is a promising research field for mitigating diseases and the pharmaceutical and food industries. It is important to monitor and minimize the appearance of aggregates in these protein products. Several methods exist to assess protein aggregation, that includes from basic investigations to advanced biophysical techniques. Physicochemical parameters such as molecular weight, conformation, structure, and dimension are examined to study aggregation. There is an urgent need to develop methods for the detection of protein aggregation and amyloid fibril formation both in vitro and in vivo. This chapter focuses on a comprehensive discussion of the methods used to characterize and evaluate aggregates and amyloid fibrils.
Topics: Amyloid; Humans; Protein Aggregates; Animals
PubMed: 38811081
DOI: 10.1016/bs.pmbts.2024.03.004 -
Cell Reports Jun 2024Protein aggregation, which can sometimes spread in a prion-like manner, is a hallmark of neurodegenerative diseases. However, whether prion-like aggregates form during...
Protein aggregation, which can sometimes spread in a prion-like manner, is a hallmark of neurodegenerative diseases. However, whether prion-like aggregates form during normal brain aging remains unknown. Here, we use quantitative proteomics in the African turquoise killifish to identify protein aggregates that accumulate in old vertebrate brains. These aggregates are enriched for prion-like RNA-binding proteins, notably the ATP-dependent RNA helicase DDX5. We validate that DDX5 forms aggregate-like puncta in the brains of old killifish and mice. Interestingly, DDX5's prion-like domain allows these aggregates to propagate across many generations in yeast. In vitro, DDX5 phase separates into condensates. Mutations that abolish DDX5 prion propagation also impair the protein's ability to phase separate. DDX5 condensates exhibit enhanced enzymatic activity, but they can mature into inactive, solid aggregates. Our findings suggest that protein aggregates with prion-like properties form during normal brain aging, which could have implications for the age-dependency of cognitive decline.
Topics: Animals; Brain; Protein Aggregates; Aging; Prions; Mice; DEAD-box RNA Helicases; Humans
PubMed: 38810650
DOI: 10.1016/j.celrep.2023.112787 -
Trends in Neurosciences May 2024Prion diseases are a group of neurodegenerative disorders caused by misfolding of proteins into pathogenic conformations that self-template to spread disease. Although... (Review)
Review
Prion diseases are a group of neurodegenerative disorders caused by misfolding of proteins into pathogenic conformations that self-template to spread disease. Although this mechanism is largely associated with the prion protein (PrP) in classical prion diseases, a growing literature indicates that other proteins, including α-synuclein, rely on a similar disease mechanism. Notably, α-synuclein misfolds into distinct conformations, or strains, that cause discrete clinical disorders including multiple system atrophy (MSA) and Parkinson's disease (PD). Because the recognized similarities between PrP and α-synuclein are increasing, this review article draws from research on PrP to identify the host and strain factors that impact disease pathogenesis, predominantly in rodent models, and focuses on key considerations for future research on α-synuclein prions.
PubMed: 38806297
DOI: 10.1016/j.tins.2024.05.004 -
Medicinal Chemistry (Shariqah (United... May 2024Alzheimer's disease, akin to coronary artery disease of the heart, is a progressive brain disorder driven by nerve cell damage.
INTRODUCTION
Alzheimer's disease, akin to coronary artery disease of the heart, is a progressive brain disorder driven by nerve cell damage.
METHOD
This study utilized computational methods to explore 14 anti-acetylcholinesterase (AChE) derivatives (1 ̶ 14) as potential treatments. By scrutinizing their interactions with 11 essential target proteins (AChE, Aβ, BChE, GSK-3β, MAO B, PDE-9, Prion, PSEN-1, sEH, Tau, and TDP-43) and comparing them with established drugs such as donepezil, galantamine, memantine, and rivastigmine, ligand 14 emerged as notable. During molecular dynamics simulations, the protein boasting the strongest bond with the critical 1QTI protein and exceeding drug-likeness criteria also exhibited remarkable stability within the enzyme's pocket across diverse temperatures (300 ̶ 320 K). In addition, we utilized density functional theory (DFT) to compute dipole moments and molecular orbital properties, including assessing the thermodynamic stability of AChE derivatives.
RESULT
This finding suggests a welldefined, potentially therapeutic interaction further supported by theoretical and future in vitro and in vivo investigations.
CONCLUSION
Ligand 14 thus emerges as a promising candidate in the fight against Alzheimer's disease.
PubMed: 38803179
DOI: 10.2174/0115734064304100240511112619