Academic literature on the topic 'Protein variants'
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Journal articles on the topic "Protein variants"
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Gai, Nan, Therese Uniacke-Lowe, Jonathan O’Regan, Hope Faulkner, and Alan L. Kelly. "Effect of Protein Genotypes on Physicochemical Properties and Protein Functionality of Bovine Milk: A Review." Foods 10, no. 10 (October 11, 2021): 2409. http://dx.doi.org/10.3390/foods10102409.
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Milk protein comprises caseins (CNs) and whey proteins, each of which has different genetic variants. Several studies have reported the frequencies of these genetic variants and the effects of variants on milk physicochemical properties and functionality. For example, the C variant and the BC haplotype of αS1-casein (αS1-CN), β-casein (β-CN) B and A1 variants, and κ-casein (κ-CN) B variant, are favourable for rennet coagulation, as well as the B variant of β-lactoglobulin (β-lg). κ-CN is reported to be the only protein influencing acid gel formation, with the AA variant contributing to a firmer acid curd. For heat stability, κ-CN B variant improves the heat resistance of milk at natural pH, and the order of heat stability between phenotypes is BB > AB > AA. The A2 variant of β-CN is more efficient in emulsion formation, but the emulsion stability is lower than the A1 and B variants. Foaming properties of milk with β-lg variant B are better than A, but the differences between β-CN A1 and A2 variants are controversial. Genetic variants of milk proteins also influence milk yield, composition, quality and processability; thus, study of such relationships offers guidance for the selection of targeted genetic variants.
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Laddach, Anna, Joseph Chi Fung Ng, and Franca Fraternali. "Pathogenic missense protein variants affect different functional pathways and proteomic features than healthy population variants." PLOS Biology 19, no. 4 (April 28, 2021): e3001207. http://dx.doi.org/10.1371/journal.pbio.3001207.
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Missense variants are present amongst the healthy population, but some of them are causative of human diseases. A classification of variants associated with “healthy” or “diseased” states is therefore not always straightforward. A deeper understanding of the nature of missense variants in health and disease, the cellular processes they may affect, and the general molecular principles which underlie these differences is essential to offer mechanistic explanations of the true impact of pathogenic variants. Here, we have formalised a statistical framework which enables robust probabilistic quantification of variant enrichment across full-length proteins, their domains, and 3D structure-defined regions. Using this framework, we validate and extend previously reported trends of variant enrichment in different protein structural regions (surface/core/interface). By examining the association of variant enrichment with available functional pathways and transcriptomic and proteomic (protein half-life, thermal stability, abundance) data, we have mined a rich set of molecular features which distinguish between pathogenic and population variants: Pathogenic variants mainly affect proteins involved in cell proliferation and nucleotide processing and are enriched in more abundant proteins. Additionally, rare population variants display features closer to common than pathogenic variants. We validate the association between these molecular features and variant pathogenicity by comparing against existing in silico variant impact annotations. This study provides molecular details into how different proteins exhibit resilience and/or sensitivity towards missense variants and provides the rationale to prioritise variant-enriched proteins and protein domains for therapeutic targeting and development. The ZoomVar database, which we created for this study, is available at fraternalilab.kcl.ac.uk/ZoomVar. It allows users to programmatically annotate missense variants with protein structural information and to calculate variant enrichment in different protein structural regions.
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Alfaro-Chávez, Ana L., Jian-Wei Liu, Joanne L. Porter, Adrian Goldman, and David L. Ollis. "Improving on nature’s shortcomings: evolving a lipase for increased lipolytic activity, expression and thermostability." Protein Engineering, Design and Selection 32, no. 1 (January 2019): 13–24. http://dx.doi.org/10.1093/protein/gzz024.
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Abstract An enzyme must be soluble, stable, active and easy to produce to be useful in industrial applications. Not all enzymes possess these attributes. We set out to determine how many changes are required to convert an enzyme with poor properties into one that has useful properties. Lipase Lip3 from Drosophila melanogaster had been previously optimised for expression in Escherichia coli. The expression levels were good, but Lip3 was mainly insoluble with poor activity. Directed evolution was used to identify variants with enhanced activity along with improved solubility. Five variants and the wild-type (wt) enzyme were purified and characterised. The yield of the wt enzyme was just 2.2 mg/L of culture, while a variant, produced under the same conditions, gave 351 mg. The improvement of activity of the best variant was 200 times higher than that of the wt when the crude lysates were analysed using pNP-C8, but with purified protein, the improvement observed was 1.5 times higher. This means that most of the increase of activity is due to increase in solubility and stability. All the purified variants showed increased thermal stability compared with the wt enzyme that had a T1/2 of 37°C, while the mutant with P291L of 42.2°C and the mutant R7_47D with five mutations had a value of 52.9°C, corresponding to an improvement of 16°C. The improved variants had between five and nine changes compared with the wt enzyme. There were four changes that were found in all 30 final round variants for which sequences were obtained; three of these changes were found in the substrate-binding domain.
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Larsen, Ole Halfdan, Alisa D. Kjaergaard, Anne-Mette Hvas, and Peter H. Nissen. "Genetic Variants in the Protein S (PROS1) Gene and Protein S Deficiency in a Danish Population." TH Open 05, no. 04 (October 2021): e479-e488. http://dx.doi.org/10.1055/s-0041-1736636.
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AbstractProtein S (PS) deficiency is a risk factor for venous thromboembolism (VTE) and can be caused by variants of the gene encoding PS (PROS1). This study aimed to evaluate the clinical value of molecular analysis of the PROS1 gene in PS-deficient participants. We performed Sanger sequencing of the coding region of the PROS1 gene and multiplex ligation-dependent probe amplification to exclude large structural rearrangements. Free PS was measured by a particle-enhanced immunoassay, while PS activity was assessed by a clotting method.A total of 87 PS-deficient participants and family members were included. In 22 index participants, we identified 13 PROS1 coding variants. Five variants were novel. In 21 index participants, no coding sequence variants or structural rearrangements were identified. The free PS level was lower in index participants carrying a PROS1 variant compared with index participants with no variant (0.51 [0.32–0.61] vs. 0.62 [0.57–0.73] × 103 IU/L; p < 0.05). The p.(Thr78Met) variant was associated with only slightly decreased free PS levels (0.59 [0.53–0.66] × 103 IU/L) compared with the p.(Glu390Lys) variant (0.27 [0.24–0.37] × 103 IU/L, p < 0.01). The frequency of VTE in participants with a coding PROS1 variant was 43 and 17% in the group with normal PROS1 gene (p = 0.05).In conclusion, we report 13 PROS1 coding variants including five novel variants. PS levels differ by PROS1 variant and the frequency of VTE was higher when a coding PROS1 variant was present. Hence, molecular analysis of the PROS1 gene may add clinical value in the diagnostic work-up of PS deficiency.
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Chang, Glenn T. G., Bart H. A. Maas, Hans K. Ploos van Amstel, Pieter H. Reitsma, Rogier M. Bertina, and Bonno N. Bouma. "Studies of the Interaction between Human Protein S and Human C4b-Binding Protein Using Deletion Variants of Recombinant Human Protein S." Thrombosis and Haemostasis 71, no. 04 (1994): 461–67. http://dx.doi.org/10.1055/s-0038-1642461.
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SummaryHuman protein S interacts noncovalently with human C4b-binding protein (C4BP). We have studied this interaction using deletion variants of recombinant human protein S. Two deletion variants were constructed by restriction enzyme digestion and in vitro site-specific mutagenesis of the human protein S cDNA. The variants were stably expressed in Cl27 cells. Recombinant proteins were purified using Fast Flow Q anion-exchange chromatography. The activated protein C (APC) cofactor activity, C4BP binding properties and reactivity to different monoclonal antibodies against human protein S were examined. The first variant (E variant), which has a deletion of the third epidermal growth factor (EGF)-like domain (deletion of exon VII, corresponding to amino acid residues ASP-160 to Asp-202) expresses normal APC cofactor • activity in a plasma system. This activity was inhibited by the addition of purified C4BP. The second variant (L variant), which has a deletion of the C-terminal loop of the sex hormone binding globulin (SHBG)- like domain (deletion of exon XV, corresponding to amino acid residues Asp-583 to Ser-635) also expresses normal APC cofactor activity in plasma. This activity could only be partially inhibited by the addition of purified C4BP.Binding of the recombinant proteins to C4BP was studied in a system using purified proteins. The E variant binds to C4BP with the same affinity similar as recombinant wild type protein S (apparent Kd ∼ 10−10 M). The L variant, however, shows a markedly reduced affinity for binding to C4BP (apparent Kd ∼ 10−7 M).Three different Ca2+-independent monoclonal antibodies (S5, S12, S17) against protein S, which do not interfere with the APC cofactor activity and C4BP binding of protein S, were used to screen the deletion variants for possible conformational changes. Two of these showed the same affinity for the E and L variant as for wild type recombinant protein S. The third, S12, which recognizes an epitope in the vicinity of ser-460, reacts normally with the E variant but has a strongly reduced affinity for the L variant, although the presence of the epitope could be clearly demonstrated by immunoblotting under denaturing conditions.This suggests that the deletion of the C-terminal loop induces a conformational change in protein S which affects the epitope for S12. Therefore although our results indicate that the C-terminal loop of the SHBG-like domain of human protein S is involved in the interaction with C4BP, we cannot exclude the possibility that the deletion of the C-terminal loop induces a conformational change that results in a loss of binding affinity for C4BP elsewhere in the protein S molecule.
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FOLSOM, JAMES P., and JOSEPH F. FRANK. "Proteomic Analysis of a Hypochlorous Acid–Tolerant Listeria monocytogenes Cultural Variant Exhibiting Enhanced Biofilm Production." Journal of Food Protection 70, no. 5 (May 1, 2007): 1129–36. http://dx.doi.org/10.4315/0362-028x-70.5.1129.
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Following exposure of Listeria monocytogenes Scott A (SA) to hypochlorous acid, rough colony variants were identified that were tolerant of hypochlorous acid and produced increased amounts of biofilm. A derivative of one of these variants was smooth, produced even more biofilm, and exhibited greater biofilm chlorine resistance. The objective of this research was to compare the protein expression of a cultural variant to SA and to identify proteins that might be associated with biofilm production and chlorine tolerance. Suspension chlorine tolerance for several cultural variants (SAR, SAR5, and SBS) was determined by exposure to 60 to 120 ppm of hypochlorous acid for 5 min. Hypochlorous acid tolerance of biofilms was determined after growing biofilms on stainless steel and then exposing them to 200 ppm of hypochlorous acid for 5 min. All cultural variants were able to survive 120 ppm of hypochlorous acid in suspension. There was little difference in the hypochlorous acid tolerance of the cultural variant planktonic cells. The cultural variants produced greater amounts of biofilm than the common form of L. monocytogenes and were more tolerant of hypochlorous acid. The SBS variant was selected for proteomic comparison because it was the variant that produced the most biofilm and was the most tolerant of hypochlorous acid when grown as a biofilm. Protein expression of planktonic and biofilm cells of SBS was compared to SA by two-dimensional difference gel electrophoresis. The 50s ribosomal protein, L10, was down-regulated in biofilm SBS. Other proteins down-regulated in planktonic SBS were the peroxide resistance protein (Dpr) and a sugar-binding protein (LMO0181). This sugar-binding protein was also up-regulated in biofilm SBS. One protein spot down-regulated in planktonic SBS contained both 50s ribosomal protein L7/L12 and an unknown protein (LMO1888).
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Overweg, Karin, Chris D. Pericone, Gerridina G. C. Verhoef, Jeffrey N. Weiser, Hugo D. Meiring, Ad P. J. M. De Jong, Ronald De Groot, and Peter W. M. Hermans. "Differential Protein Expression in Phenotypic Variants of Streptococcus pneumoniae." Infection and Immunity 68, no. 8 (August 1, 2000): 4604–10. http://dx.doi.org/10.1128/iai.68.8.4604-4610.2000.
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ABSTRACT Streptococcus pneumoniae undergoes spontaneous phase variation resulting in opaque and transparent colony forms. Differences in colony opacity correlate with differences in virulence: the transparent variants are more capable of colonizing the nasopharynx, whereas the opaque variants show increased virulence during systemic infections. To gain insight into the pathogenesis of pneumococcal disease at the molecular level, protein expression patterns of the phenotypic variants of two pneumococcal strains were compared by high-resolution two-dimensional protein electrophoresis. In comparison with transparent variants, the opaque variants reduced the expression of two proteins and overexpressed one protein. The proteins were identified by mass spectrometric analysis. The protein overexpressed in the opaque phenotype revealed significant homology to elongation factor Ts of Helicobacter pylori. One of the two proteins that were underexpressed in the opaque variants revealed significant homology to the proteinase maturation protein PrtM ofLactocobacillus paracasei, a member of the family of peptidyl-prolyl cis/trans isomerases. A consensus lipoprotein signal sequence suggests that the putative proteinase maturation protein A, designated PpmA, is located at the surface of the pneumococcus and may play a role in the maturation of surface or secreted proteins. The second underexpressed protein was identified as pyruvate oxidase, SpxB. The lower SpxB expression in opaque variants most probably explains the reduced production of hydrogen peroxide, a reaction product of SpxB, in this variant. Since aspxB-defective pneumococcal mutant has decreased ability to colonize the nasopharynx (B. Spellerberg, D. R. Cundell, J. Sandros, B. J. Pearce, I. Idanpaan-Heikkila, C. Rosenow, and H. R. Masure, 1996. Mol. Microbiol. 19:803–813, 1996), our data suggest that SpxB plays an important role in enhancing the ability of transparent variants to efficiently colonize the nasopharynx.
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Thorne, Lucy G., Mehdi Bouhaddou, Ann-Kathrin Reuschl, Lorena Zuliani-Alvarez, Ben Polacco, Adrian Pelin, Jyoti Batra, et al. "Evolution of enhanced innate immune evasion by SARS-CoV-2." Nature 602, no. 7897 (December 23, 2021): 487–95. http://dx.doi.org/10.1038/s41586-021-04352-y.
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AbstractThe emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant3 suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6—all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection4. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants.
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Soorajkumar, Anjana, Ebrahim Alakraf, Mohammed Uddin, Stefan S. Du Plessis, Alawi Alsheikh-Ali, and Richard K. Kandasamy. "Computational Analysis of Short Linear Motifs in the Spike Protein of SARS-CoV-2 Variants Provides Possible Clues into the Immune Hijack and Evasion Mechanisms of Omicron Variant." International Journal of Molecular Sciences 23, no. 15 (August 8, 2022): 8822. http://dx.doi.org/10.3390/ijms23158822.
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Short linear motifs (SLiMs) are short linear sequences that can mediate protein–protein interaction. Mimicking eukaryotic SLiMs to compete with extra- or intracellular binding partners, or to sequester host proteins is the crucial strategy of viruses to pervert the host system. Evolved proteins in viruses facilitate minimal protein–protein interactions that significantly affect intracellular signaling networks. Unfortunately, very little information about SARS-CoV-2 SLiMs is known, especially across SARS-CoV-2 variants. Through the ELM database-based sequence analysis of spike proteins from all the major SARS-CoV-2 variants, we identified four overriding SLiMs in the SARS-CoV-2 Omicron variant, namely, LIG_TRFH_1, LIG_REV1ctd_RIR_1, LIG_CaM_NSCaTE_8, and MOD_LATS_1. These SLiMs are highly likely to interfere with various immune functions, interact with host intracellular proteins, regulate cellular pathways, and lubricate viral infection and transmission. These cellular interactions possibly serve as potential therapeutic targets for these variants, and this approach can be further exploited to combat emerging SARS-CoV-2 variants.
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Moghaddar, Mehrnoosh, Ramtin Radman, and Ian Macreadie. "Severity, Pathogenicity and Transmissibility of Delta and Lambda Variants of SARS-CoV-2, Toxicity of Spike Protein and Possibilities for Future Prevention of COVID-19." Microorganisms 9, no. 10 (October 18, 2021): 2167. http://dx.doi.org/10.3390/microorganisms9102167.
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The World Health Organization reports that SARS-CoV-2 has infected over 220 million people and claimed over 4.7 million lives globally. While there are new effective vaccines, the differences in behavior of variants are causing challenges in vaccine development or treatment. Here, we discuss Delta, a variant of concern, and Lambda, a variant of interest. They demonstrate high infectivity and are less responsive to the immune response in vaccinated individuals. In this review, we briefly summarize the reason for infectivity and the severity of the novel variants. Delta and Lambda variants exhibit more changes in NSPs proteins and the S protein, compared to the original Wuhan strain. Lambda also has numerous amino acid substitutions in NSPs and S proteins, plus a deletion in the NTD of S protein, leading to partial escape from neutralizing antibodies (NAbs) in vaccinated individuals. We discuss the role of furin protease and the ACE2 receptor in virus infection, hotspot mutations in the S protein, the toxicity of the S protein and the increased pathogenicity of Delta and Lambda variants. We discuss future therapeutic strategies, including those based on high stability of epitopes, conservation of the N protein and the novel intracellular antibody receptor, tripartite-motif protein 21 (TRIM21) recognized by antibodies against the N protein.
Dissertations / Theses on the topic "Protein variants"
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Sadler, David Paul. "Mechanically unfolding variants of protein L." Thesis, University of Leeds, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444035.
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Jones, Kerrie Margaret. "Mutational variants of E. coli glutamate dehydrogenase." Thesis, University of Leeds, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278229.
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Lee, Seung-Joo. "Structural and functional consequences of disease-related protein variants." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1269545015.
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Veltman, Oene Robert. "Engineering high performance variants of Bacillusthermolysin-like proteases." [S.l. : [Groningen] : s.n.] ; [University Library Groningen] [Host], 1997. http://irs.ub.rug.nl/ppn/164267484.
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Bruce, Lesley J. "A study of human erythrocyte band 3 variants." Thesis, University of Bristol, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240590.
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Waterhouse, Mark Peter. "Specific targeting of FcγRIIIa using artificial scaffold protein variants." Thesis, University of Leeds, 2018. http://etheses.whiterose.ac.uk/20522/.
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Fcγ Receptors (FcγRs) are cell-surface receptors for IgG that are expressed on immune cells including macrophages, monocytes and natural killer (NK) cells. Upon binding to IgG-containing immune complexes, FcγRs trigger cell-mediated effector functions that lead to the clearance of pathogenic material and immune homeostasis. However, aberrant activation of these pathways can result in autoimmune susceptibility and, as such, FcγRs are implicated in the pathogenesis of several autoimmune disorders. For example, FcγRIIIa, expressed on macrophages and NK cells, has been functionally and genetically linked to susceptibility for rheumatoid arthritis and is a valid target for several FcγR-mediated autoimmune disorders. Despite this, FcγRIIIa is currently under-exploited due to a lack of FcγRIIIa-specific agents, which results from the expression of the near identical FcγRIIIb on neutrophils. However, several FcγRIIIa-specific Adhirons (an engineered protein scaffold) have recently been described, which inhibit IgG binding and effector functions (phagocytosis and cytokine release) of THP-1 cells. This thesis aimed to fully characterise and enhance the properties of one of these recently described Adhirons (known as AdG3) through site-directed mutagenesis (SDM); Molecular Dynamics (MD) simulations; and fusion to the IgG1- or IgG2-Fc. SDM identified several key binding residues in the AdG3 variable regions through screening of AdG3 mutants by surface plasmon resonance (SPR). SPR also identified three mutants with enhanced affinity for FcγRIIIa and showed that AdG3 possesses background binding to the highly homologous FcγRIIIbNA1, but not FcγRIIIbNA2, which was supported by MD simulations that revealed the exquisite mode of AdG3 specificity for these receptors, which was mediated through the Arg18Ser polymorphism in the AdG3 binding site. Fusion to the IgG-Fc was not detrimental to the FcγRIIIa-AdG3 interaction, and fusion to the IgG2-Fc was observed to potentially enhance the affinity and specificity of AdG3 for FcγRIIIa. These findings could subsequently be utilised for further improvement of AdG3 affinity and specificity, as well as other clinically relevant parameters such as serum half-life.
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Rivas, Cruz Manuel A. "Medical relevance and functional consequences of protein truncating variants." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:a042ca18-7b35-4a62-aef0-e3ba2e8795f7.
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Genome-wide association studies have greatly improved our understanding of the contribution of common variants to the genetic architecture of complex traits. However, two major limitations have been highlighted. First, common variant associations typically do not identify the causal variant and/or the gene that it is exerting its effect on to influence a trait. Second, common variant associations usually consist of variants with small effects. As a consequence, it is more challenging to harness their translational impact. Association studies of rare variants and complex traits may be able to help address these limitations. Empirical population genetic data shows that deleterious variants are rare. More specifically, there is a very strong depletion of common protein truncating variants (PTVs, commonly referred to as loss-of-function variants) in the genome, a group of variants that have been shown to have large effect on gene function, are enriched for severe disease-causing mutations, but in other instances may actually be protective against disease. This thesis is divided into three parts dedicated to the study of protein truncating variants, their medical relevance, and their functional consequences. First, I present statistical, bioinformatic, and computational methods developed for the study of protein truncating variants and their association to complex traits, and their functional consequences. Second, I present application of the methods to a number of case-control and quantitative trait studies discovering new variants and genes associated to breast and ovarian cancer, type 1 diabetes, lipids, and metabolic traits measured with NMR spectroscopy. Third, I present work on improving annotation of protein truncating variants by studying their functional consequences. Taken together, these results highlight the utility of interrogating protein truncating variants in medical and functional genomic studies.
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Baldan, Nikita <1996>. "Computational analysis of NaV1.7 protein variants and tool for 3D visualization of protein structures." Master's Degree Thesis, Università Ca' Foscari Venezia, 2020. http://hdl.handle.net/10579/17572.
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This thesis is composed of two parts. The first part explores the possibility to use Graph Kernels to discriminate pathogenic versus non-pathogenic variants of a specific protein.
All variants are represented as Residue Interaction Networks (RIN), where nodes are amino acids and edges represent non-covalent bonds between atoms of the two involved amino acids.
This part is guided by a previous Master degree thesis that considered protein NaV1.7, which is responsible for the transmission of the pain signal from the peripheral nervous system to the brain. The thesis considered 85 genetic variants of the human NaV1.7, among which 30 are known to cause neuropathic diseases and 55 are instead neutral.
The results of the first part highlight that some Graph Kernels are actually able to discriminate between pathogenic and neutral variants.
This prompted the idea of realizing a 3D viewer able to show the three-dimensional structure of a protein and also its non-covalent bonds.
The second part of the thesis describes Spheremole, an application for the visualization of the three-dimensional structure of a protein. In particular, Spheremole allows the visualization of two proteins structures and their visual comparison, also based on their non-covalent bonds.
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Norman, Jane Eleanor. "Molecular mechanisms of platelet G protein-coupled receptor gene variants." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.687283.
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G protein-coupled receptors (GPCRs) are critical mediators of platelet responses to regulatory agonists and are essential drug targets. This project aimed to identify informative platelet GPCR gene variants and to characterise the mechanism of loss of receptor function for selected variants. Variants were sought in 2400 cardiac surgery patients in which preoperative platelet function test results were used to select subgroups with GPCR dysfunction potentially explained by loss of function P2Y12 receptor, thromboxane A2 receptor and protease-activated receptor 1 gene variants. This approach did not identify variants likely to affect GPCR function. Re-sequencing the protease-activated receptor 4 (PAR4) gene yielded seven different missense variants. After evaluation using computational prediction and homology modelling, the predicted tyrosine 157 to cysteine (Y157C) substitution was demonstrated to reduce PAR4 reactivity and was studied further. Compared to controls, Y157C platelets showed reduced functional responses to PAR4 activating peptide and a greater reduction in responses to a-thrombin in the presence of a PAR1 antagonist, vorapaxar, together consistent with a PAR4 defect. Y157C platelets, showed similar total PAR4 expression levels to controls but reduced surface expression, accounting at least in part for the reduced of PAR4 reactivity. HEK293 cells transfected with a PAR4 Y157C expression construct also showed reduced PAR4 surface expression and functional responses. PAR4 Y157C co-localised with an ER marker in the cell cytoplasm and had an expression pattern consistent with reduced N-glycosylation. Mutagenesis of the putative hydrogen bond partner for the substituted Y157 residue caused a similar phenotype. These findings suggest the Y157C substitution results in receptor mis-trafficking due to a disruption of an intra-molecular hydrogen bond. This first reported characterisation of a variant affecting PAR4 demonstrates that rare variants in the PAR4 gene are a potential source of inter-individual variation in the platelet haemostatic response and the effect of anti-platelet drugs that target the PAR system.
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Yang, Su jeong. "Biochemical and biophysical characterisation of allelic variants of ovine prion protein." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611255.
Full textBooks on the topic "Protein variants"
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Estrada, Sergio. Cystatin A, a mammalian cysteine proteinase inhibitor: Mechanism of inhibition of target proteinases by recombinant cystatin A variants. Uppsala: Sveriges Lantbruksuniversitet, 1998.
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Privitera, Salvatore. Construction and functional characterization of a cDNA clone for the spliced variant of gbs-galactosidase and further evidence that it encodes the elastin/laminin binding protein, EBP. Ottawa: National Library of Canada = Bibliothèque nationale du Canada, 1999.
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Janssens, Veerle. Promoter Analysis and Characterization of Novel Splice Variants of the Human Phosphotyrosyl Phosphatase Activator Gene. Leuven Univ Pr, 2000.
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Heng, Liang. Characterization of the folding and stability of the Escherichia coli bacteriophage f1 gene V protein and its variants. 1992.
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Focosi, Daniele. SARS-CoV-2 Spike Protein Convergent Evolution: Impact of Virus Variants on Efficacy of COVID-19 Therapeutics and Vaccines. Springer International Publishing AG, 2021.
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Ng, Dominic S. Familial Apolipoprotein A-I Deficiency. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0036.
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Apolipoprotein (apo) A-I is the key structural protein of high-density lipoprotein (HDL) and is necessary for sustaining the circulating level of HDL. It has also been studied extensively for its role in mediating many of the antiatherosclerotic and antithrombotic properties of HDL. More than 50 naturally occurring mutations and variants have been described, and they usually result in marked HDL deficiency in a gene-dose dependent manner. However, the propensity to develop accelerated coronary heart disease (CHD) is highly heterogeneous. Mutations resulting in inability to synthesize apo A-I tend to be associated with early CHD, while mutations resulting in structurally altered apo A-I are generally not associated. Furthermore, a number of apo A-I variants, for example apo A-I Iowa or apo A-I Helsinki, have been linked to amyloidosis, resulting in potentially serious morbid complications.
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Chess, Andrew, and Schahram Akbarian. The Human Brain and its Epigenomes. Edited by Dennis S. Charney, Eric J. Nestler, Pamela Sklar, and Joseph D. Buxbaum. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190681425.003.0003.
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Conventional psychopharmacology elicits an insufficient therapeutic response in more than one half of patients diagnosed with schizophrenia, bipolar disorder, depression, anxiety, or related disorders. This underscores the need to further explore the neurobiology and molecular pathology of mental disorders in order to develop novel treatment strategies of higher efficacy. One promising avenue of research is epigenetics.Deeper understanding of genome organization and function in normal and diseased human brain will require comprehensive charting of neuronal and glial epigenomes. This includes DNA cytosine and adenine methylation, hundred(s) of residue-specific post-translational histone modifications and histone variants, transcription factor occupancies, and chromosomal conformations and loopings. Epigenome mappings provide an important avenue to assign function to many risk-associated DNA variants and mutations that do not affect protein-coding sequences. Powerful novel single cell technologies offer the opportunity to understand genome function in context of the vastly complex cellular heterogeneity and neuroanatomical diversity of the human brain.
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Thompson, Miles. Characterization of variant forms of G protein-coupled receptors. 2003.
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Slack, Jonathan. Conclusion. Oxford University Press, 2014. http://dx.doi.org/10.1093/actrade/9780199676507.003.0007.
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There are many concepts of the gene. They range from defined sequences of DNA encoding proteins, to variant genes distinguishing individuals (markers), to unknown genes controlling quantitative traits, to hypothetical entities controlling behaviour as well as other complex characteristics. The science of genes is at its most precise and reliable when dealing with known protein coding genes. But all of the different concepts of the gene have been and continue to be important in numerous areas of human thought.
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Wan, Simmy C. T. Studies of variant SHP-1 protein tyrosine phosphatases in human epithelial cells. 2004.
Find full textBook chapters on the topic "Protein variants"
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Wong, Tuck Seng, and Kang Lan Tee. "Continuing from Protein Variants." In A Practical Guide to Protein Engineering, 187–95. Cham: Springer International Publishing, 2020. http://dx.doi.org/10.1007/978-3-030-56898-6_11.
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Medway, Christopher, and Kevin Morgan. "CD2-Associated Protein (CD2AP)." In Genetic Variants in Alzheimer's Disease, 201–8. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-7309-1_11.
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Vazquez, Miguel, and Tirso Pons. "Annotating Cancer-Related Variants at Protein–Protein Interface with Structure-PPi." In Variant Calling, 315–30. New York, NY: Springer US, 2022. http://dx.doi.org/10.1007/978-1-0716-2293-3_20.
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Wong, Tuck Seng, and Kang Lan Tee. "Protein Variants Analysis and Characterization." In A Practical Guide to Protein Engineering, 169–86. Cham: Springer International Publishing, 2020. http://dx.doi.org/10.1007/978-3-030-56898-6_10.
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Harris, H., Elizabetbh B. Robson, and M. Siniscalco. "Genetics of the Plasma Protein Variants." In Ciba Foundation Symposium - Regulation of Cell Metabolism, 151–77. Chichester, UK: John Wiley & Sons, Ltd, 2008. http://dx.doi.org/10.1002/9780470719145.ch11.
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Harris, H., Elizabeth B. Robson, and M. Siniscalco. "Genetics of the Plasma Protein Variants." In Ciba Foundation Symposium - Biochemistry of Human Genetics, 151–77. Chichester, UK: John Wiley & Sons, Ltd, 2008. http://dx.doi.org/10.1002/9780470719152.ch11.
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Henschen, A. "Two thousand years of fibrinogen research and evidence for fibrin being the first protein." In Structural variants and interactions, edited by A. Henschen and B. Henssel, 1–8. Berlin, Boston: De Gruyter, 1985. http://dx.doi.org/10.1515/9783110855951-002.
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Magnusson, S., S. C. Bock, and K. Skriver. "C1̄ Inhibitor: Structure, Genetic Variants and Serpin Homologies." In Methods in Protein Sequence Analysis, 301–11. Basel: Birkhäuser Basel, 1991. http://dx.doi.org/10.1007/978-3-0348-5678-2_31.
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Ludwig, Richard, Jacob Bongers, Li Tao, Yunping Huang, Jinmei Fu, Wei Wu, Peiran Liu, Hangtian Song, and Reb Russell. "Molecular Variants Characterization in Protein Therapeutics Development." In Characterization of Protein Therapeutics using Mass Spectrometry, 207–77. Boston, MA: Springer US, 2013. http://dx.doi.org/10.1007/978-1-4419-7862-2_6.
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Baker, Darren P., Frederick R. Taylor, and R. Blake Pepinsky. "Purifying the Hedgehog Protein and its Variants." In Methods in Molecular Biology, 1–22. Totowa, NJ: Humana Press, 2007. http://dx.doi.org/10.1007/978-1-59745-516-9_1.
Full textConference papers on the topic "Protein variants"
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"Emergence of SARS-CoV-2 Variant of Concern Omicron: Biological Features and Genomic Concern." In International Conference on Public Health and Humanitarian Action. International Federation of Medical Students' Associations - Jordan, 2022. http://dx.doi.org/10.56950/itrx2370.
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Abstract Corona virus infection is a worldwide health threat that has infected a substantial portion of the world's population and is caused by SARS-CoV-2. It is the natural tendency of a virus to change the genetic makeup through the point mutation, and such viruses are called the variant of the original virus. SARS-CoV-2 virus also undergoes such mutation (may be one or more and distinct from other) over time, and many genetically diverse variant has risen. Such variants might be of variants of concern (VOC) and variant of interest (VOI) based on the differences in virulence, transmissibility, pathogenicity, and vaccination efficacy. Omicron, a new VOC of SARS-CoV-2, has recently emerged as a global distress to more than 115 countries. The article provides a summary of the evolutionary, biological, and genomic aspects of different SARS-CoV-2 VOC with respect to Omicron and found that amino acid mutation in spike proteins such as A67V, Δ69-70, Q954H, N969K, L981F etc and other structural protein mutations such as D3G, Q19E, A63T in membrane protein, T9I in envelope protein and P13L, Δ31-33, R203K, G204R in nucleocapsid protein results major differences between different VOC/VOI of SARS-CoV-2. Further, effectiveness of the widely used SARS-CoV-2 vaccines has been reviewed specific to Omicron. The existing available COVID-19 vaccines developed and manufactured by Pfizer, AstraZeneca, Johnson & Johnson, Moderna, and Novavax show reduced efficacy against the latest VOC of SARS- CoV-2 Omicron. Based on the available literature of preliminary findings, people who get a booster shot or a third vaccine dosage may have better protected against Omicron. Keywords: SARS-CoV-2, Omicron, Variants of Concern, Variants of Interest, Mutation, Vaccine.
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Sar, Enakshi, and Sriyankar Acharyya. "Genetic algorithm variants in Predicting Protein Structure." In 2014 International Conference on Communications and Signal Processing (ICCSP). IEEE, 2014. http://dx.doi.org/10.1109/iccsp.2014.6949854.
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Khaliullin, Eldar, Vladimir Drachev, Mark Thoreson, V. Jo Davisson, Meena Narsimhan, Dor Ben-Amotz, and Vladimir M. Shalaev. "Protein sensing with SERS: insulin variants and phosphorylation detection." In Frontiers in Optics. Washington, D.C.: OSA, 2004. http://dx.doi.org/10.1364/fio.2004.ftue2.
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Boisson, J. C., L. Jourdan, E. G. Talbi, and C. Rolando. "A preliminary work on evolutionary identification of protein variants and new proteins on grids." In 20th International Conference on Advanced Information Networking and Applications - Volume 1 (AINA'06). IEEE, 2006. http://dx.doi.org/10.1109/aina.2006.48.
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Poort, S. R., C. Krommenhoek-van Es, I. K. van der Linden, N. H. van Tilburg, and R. M. Bertina. "DEFECTS OF VITAMIN K-DEPENDENT FACTORS IN CA(11)-STABILI ZED STRUCTURE." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644320.
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Vitamin K-dependent (anti)coagulation factors (factor II, VII, IX, X protein C and S) undergo a conformational transition upon binding of Ca(II), which is a prerequisite for their normal function. Abnormalities in these properties occur during vitamin K deficiency or treatment with anti vitamin K drugs and in some genetic variants of coagulation factors. Immunological assays utilizing antibodies against the Ca(II)-stabilized structure are useful to detect such abnormalities.Starting from specific rabbit antisera antibody populations specific for the Ca(II)-dependent conformation of factor II, VII, IX, X and protein C and S were isolated using immuno-affinity procedures. Subsequently immunoradiometric assays specific for the Ca(II)-dependent (Ca(II)Ag) and Ca(II)-independent (NonCa(II)Ag) conformations of the different proteins were developed. These assays were used for the analysis of plasmas of patients stably treated with oral anticoagulants; Ca(II)Ag, NonCa(II)Ag and their ratio were measured as function of the intensity of the treatment (INR 2.4 to 4.8). The same parameters were measured in plasmas of patients with hereditary coagulation disorders. After treatment with oral anticoagulation with an antivitamin K drug reduced ratios of Ca(II)Ag/-NonCa(II)Ag were observed for factor II, VII, IX, protein C and protein S. However, the actual degree of reduction and its dependence on the intensity of treatment varied for the different vitamin K-dependent proteins. In general Ca(II)Ag levels correspond nicely with the procoagulant activity of the concerning proteins. These data provide indirect evidence for the existence of abnormal (non and/or subcarboxylated) forms of the vitamin K-dependent proteins during oral anticoagulant treatment.Genetic variants with a mutation in one of the sites involved in the formation of the Ca(II)-s tab i1ized structure could be detected for factor IX, factor VII and factor II. However, the extent of reduction of the ratio Ca(II)Ag/-NonCa(II)Ag differed considerably in those variants.
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Azmi, Muhammad Bilal. "In Silico Basis to Understand the Molecular Interaction of Human NNATGene With Therapeutic Compounds of Anorexia Nervosa." In INTERNATIONAL CONFERENCE ON BIOLOGICAL RESEARCH AND APPLIED SCIENCE. Jinnah University for Women, Karachi,Pakistan, 2022. http://dx.doi.org/10.37962/ibras/2022/1-2.
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Introduction: Anorexia nervosa (AN)– a perplexing heritable, psychiatric eating disorder condition characterized by low body weight. The prevalence of AN is found to be high in younger age adults with a raised mortality rate. Genetic studies have been insufficient in identifying the role of specific genes that predispose an individual to AN. Objectives: The objective was to explore the role of NNAT (neuronatin) gene variants and its structure based molecular interactions with therapeutic compounds of AN. To investigate the role of structural missense pathogenic variants (SNPs: single nucleotide polymorphism) or change in the expression of NNAT with possibility of AN. Methodology: NNAT gene protein coding sequence, SNPs were extracted and validated from public databases. Gene to gene interactions, protein localization and human tissue-specific expression analysis of NNAT gene showed highest tissue-specific expression in the brain. Estimates of functional impact of SNPs using transcript sequence and machine learning based approaches (in silico algorithms) were computed to investigate the pathogenicity and protein stability of NNAT variants. Sequence alignment, ab initio 3D structure-modeling of wild-type, validation and recognition of binding cavities of NNAT through in silico web based tools were performed. Alternate model prediction for NNAT variants through residue specific mutation approach and structural validation were also done through Chimera tool. The 3D compounds involved in the management of AN were extracted from the Drug Bank database, afterwards energy minimization and rule of drug-likeness were performed. The eligible 3D compounds were docked with identified variants, to evaluate the drugs binding molecular mechanics. Results & Conclusion: Overall, 10 NNAT missense variants were extracted on the basis of minor allele frequency (MAF < 0.001) and other consequence types. Further three variants were selected among ten according to the transcript sequence, which includesrs542858994 (F26L), rs539681368 (C30Y) and rs542858994 (F53L). Structures for these variants’ protein were generated, validated and docked with AN drugs. The functional impact analyses of selected missense SNPs of NNAT showed high risk pathogenicity and can cause changes in the physical and chemical properties of amino acids, thus affecting the function of protein. The computation of binding energies of variants of NNAT with AN compounds strengthen the hypothesis that these variants strongly interact with the AN drugs, hence reducing the level of free NNAT as well as target drugs, for neuronal functioning. Therefore, constitutionally reduced level of NNAT and binding of NNAT variants with AN drugs may serve as the basis to increases the susceptibility towards AN.
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Illuzzi, Jennifer, Nicole A. Harris, Brittney A. Manvilla, Daemyung Kim, Mengxia Li, Alexander C. Drohat, and David M. Wilson. "Abstract 2388: Deciphering the role of APE1 protein variants in disease etiology." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-2388.
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Radbel, J. M., K. Vayas, E. Abramova, O. Le-Hoang, V. Sunil, A. Gow, and D. L. Laskin. "Surfactant Protein D Variants in Sepsis-Induced Lung Injury Following Ozone Exposure." In American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a6153.
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Nedelkov, Dobrin, Olgica Trenchevska, Aleksandra Pupinoska, David Phillips, Elena Kamcheva, Slobodanka Romevska, and Urban A. Kiernan. "Abstract 5114: Mass spectrometric immunoassays for quantitative determination of protein biomarker variants." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-5114.
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Mihalcea, Elena, Gabi Drochioiu, Stefania-Claudia Jitaru, Violeta Mangalagiu, and Robert �Vasile Gradinaru. "PROTEIN AND PEPTIDE DETERMINATION BASED ON THE MODIFIED BIURET PROCEDURE: IMPLICATIONS FOR VARIOUS BIOTECHNOLOGIES." In 22nd SGEM International Multidisciplinary Scientific GeoConference 2022. STEF92 Technology, 2022. http://dx.doi.org/10.5593/sgem2022/6.1/s25.14.
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Spectrophotometric methods for total protein analysis are generally simple, rapid and sensitive. Such sensitive protein assays may have applications in forensic science, in the detection of protein contaminants in drugs and in a number of other applications of research interest. Biuret reaction with proteins and peptides is widely used in clinical and biological laboratories. In this work, instead of copper sulphate, sodium hydroxide and Seignette salt, we used insoluble copper phosphate, potassium or sodium hydroxide and ethyl alcohol for the preparation of the biuret reagent. Absorbance of the biuret complex was recorded both at 219-230 nm (after dilution) and around 550 nm against a reagent blank. Amino acid interference was investigated around 550 nm at the same concentration as proteins. The sensitivity of the method at 226 nm was greater than those of other spectrophotometric assays (old biuret method, Lowry, and BCA) with a LOD of about 0.5 �g mL?1 BSA. The new variants of the biuret method for total protein analysis eliminate the need for precise reagent addition and vortexing inherent in the widely used Lowry method, providing flexibility of application. The method developed, which uses an alkaline-alcoholic reagent and insoluble copper phosphate, is simple, rapid, reproducible and sensitive; it is not influenced by detergents, solvents and buffers containing ammonium and is flexible enough to change the analytical protocol when necessary. A discussion was made on the applications of protein and peptide determination with the new biuret assay.
Reports on the topic "Protein variants"
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Dolja, Valerian V., Amit Gal-On, and Victor Gaba. Suppression of Potyvirus Infection by a Closterovirus Protein. United States Department of Agriculture, March 2002. http://dx.doi.org/10.32747/2002.7580682.bard.
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The plant virus family Polyviridae is the largest and most destructive of all plant viruses. Despite the continuous effort to develop resistant plant varieties, there is a desperate need for novel approaches conferring wide-range potyvirus resistance. Based on experiments with the tobacco etch potyvirus (TEV)-derived gene expression vector, we suggested approach for screening of the candidate resistance genes. This approach relies on insertion of the genes into a virus vector and evaluation of the phenotypes of the resulting recombinant viruses. The genes which suppress infection by the recombinant virus are selected as candidates for engineering transgenic resistance. Our analysis of the TEV variants expressing proteins of the beet yellows closterovirus (BYV) revealed that one of those, the leader proteinase (L-Pro), strongly and specifically interfered with the hybrid TEV infection. Since closterovirus L-Pro is evolutionary related to potyviral helper component-proteinase (HC-Pro), we suggested that the L-Pro interfered with HC-Pro function via a trans-dominant inhibitory effect. Based on these findings, we proposed to test two major hypotheses. First, we suggested that L-Pro-mediated suppression of potyvirus infection is a general phenomenon effective against a range of potyviruses. The second hypothesis stated that the suppression effect can be reproduced in transgenic plants expressing L-Pro, and can be utilized for generation of resistance to potyviruses. In accord with these hypotheses, we developed two original objectives of our proposal: A) to determine the range of the closterovirus-derived suppression of potyviral infection, and B) to try and utilize the L-Pro-mediated suppression for the development of transgenic resistance to potyviruses. In the first phase of the project, we have developed all major tools and technologies required for successful completion of the proposed research. These included TEV and ZYMV vectors engineered to express several closteroviral L-Pro variants, and generation of the large collection of transgenic plants. To our satisfaction, characterization of the infection phenotypes exhibited by chimeric TEV and ZYMV variants confirmed our first hypothesis. For instance, similar to TEV-L- Pro(BYV) chimera, ZYMV-L-Pro(LIYV) chimera was debilitated in its systemic spread. In contrast, ZYMV-GUS chimera (positive control) was competent in establishing vigorous systemic infection. These and other results with chimeric viruses indicated that several closteroviral proteinases inhibit long-distance movement of the potyviruses upon co-expression in infected plants. In order to complete the second objective, we have generated ~90 tobacco lines transformed with closteroviral L-Pro variants, as well as ~100 lines transformed with BYV Hsp70-homolog (Hsp70h; a negative control). The presence and expression of the trans gene in each line was initially confirmed using RT-PCR and RNA preparations isolated from plants. However, since detection of the trans gene-specific RNA can not guarantee production of the corresponding protein, we have also generated L-Pro- and Hsp70h-specific antisera using corresponding synthetic peptides. These antisera allowed us to confirm that the transgenic plant lines produced detectable, although highly variable levels of the closterovirus antigens. In a final phase of the project, we tested susceptibility of the transgenic lines to TEV infection. To this end, we determined that the minimal dilution of the TEV inoculum that is still capable of infecting 100% of nontransgenic plants was 1:20, and used 10 plants per line (in total, ~2,000 plants). Unfortunately, none of the lines exhibited statistically significant reduction in susceptibility. Although discouraging, this outcome prompted us to expand our experimental plan and conduct additional experiments. Our aim was to test if closteroviral proteinases are capable of functioning in trans. We have developed agroinfection protocol for BYV, and tested if co- expression of the L-Pro is capable of rescuing corresponding null-mutant. The clear-cut, negative results of these experiments demonstrated that L-Pro acts only in cis, thus explaining the lack of resistance in our transgenic plants. We have also characterized a collection of the L-Pro alanine- scanning mutants and found direct genetic evidence of the requirement for L-Pro in virus systemic spread. To conclude, our research supported by BARD confirmed one but not another of our original hypotheses. Moreover, it provided an important insight into functional specialization of the viral proteinases and generated set of tools and data with which we will be able to address the molecular mechanisms by which these proteins provide a variety of critical functions during virus life cycle.
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Brayton, Kelly A., Varda Shkap, Guy H. Palmer, Wendy C. Brown, and Thea Molad. Control of Bovine Anaplasmosis: Protective Capacity of the MSP2 Allelic Repertoire. United States Department of Agriculture, January 2014. http://dx.doi.org/10.32747/2014.7699838.bard.
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Anaplasmosis is an arthropod-borne disease of cattle caused by the rickettsia Anaplasmamarginale and is an impediment to efficient production of healthy livestock in both Israel and the United States. Currently, the only effective vaccines are derived from the blood of infected cattle. The risk of widespread transmission of both known and newly emergent pathogens has prevented licensure of live blood-based vaccines in the U.S. and is a major concern for their continued use in Israel. Consequently, development of a safe, effective vaccine is a high priority. Despite its drawbacks as a live, blood-based vaccine, the Israel vaccine strain protects against disease upon challenge with wild-type A. marginale in extensive experimental trials and during 50 years of deployment in Israel. Field studies in Australia and Argentina indicate that this protection is broadly effective. Thus, to identify antigens for development of a safe and effective recombinant vaccine, we have used a comparative genomics approach by sequencing the Israel vaccine strain and searching for shared surface antigens with sequenced wild-type U.S. strains. We have focused on Msp2, the immune-dominant but antigenically variable surface protein, based on shared structure among strains and demonstration that antibody from cattle immunized with the Israel vaccine strain binds Msp2 from the genetically and geographically distinct U.S. St. Maries strain, consistent with the ability to protect against St. Maries challenge. Importantly, we have defined the full repertoire of Msp2 simple variants encoded by the vaccine strain and hypothesize that a recombinant vaccine encoding this full repertoire will induce protection equivalent to that induced by the live vaccine strain. Any escape from immunity by generation of complex Msp2 variants is predicted to carry a severe fitness cost that prevents high-level bacteremia and disease— consistent with the type of protection induced by the live vaccine strain. We tested the hypothesis that the Msp2 simple variant repertoires in wild-type A. marginale strains are recognized by antibody from cattle immunized with the Israel vaccine strain and that immunization with the vaccine strain Msp2 repertoire can recapitulate the protection provided by the vaccine strain upon challenge with Israel and U.S. strains of A. marginale. Our findings demonstrate that a set of conserved outer membrane proteins are recognized by immune serum from A. centrale vaccinated animals but that this set of proteins does not include Msp2. These findings suggest that “subdominant” immunogens are required for vaccine induced protection.
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Weller, Joel I., Derek M. Bickhart, Micha Ron, Eyal Seroussi, George Liu, and George R. Wiggans. Determination of actual polymorphisms responsible for economic trait variation in dairy cattle. United States Department of Agriculture, January 2015. http://dx.doi.org/10.32747/2015.7600017.bard.
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The project’s general objectives were to determine specific polymorphisms at the DNA level responsible for observed quantitative trait loci (QTLs) and to estimate their effects, frequencies, and selection potential in the Holstein dairy cattle breed. The specific objectives were to (1) localize the causative polymorphisms to small chromosomal segments based on analysis of 52 U.S. Holstein bulls each with at least 100 sons with high-reliability genetic evaluations using the a posteriori granddaughter design; (2) sequence the complete genomes of at least 40 of those bulls to 20 coverage; (3) determine causative polymorphisms based on concordance between the bulls’ genotypes for specific polymorphisms and their status for a QTL; (4) validate putative quantitative trait variants by genotyping a sample of Israeli Holstein cows; and (5) perform gene expression analysis using statistical methodologies, including determination of signatures of selection, based on somatic cells of cows that are homozygous for contrasting quantitative trait variants; and (6) analyze genes with putative quantitative trait variants using data mining techniques. Current methods for genomic evaluation are based on population-wide linkage disequilibrium between markers and actual alleles that affect traits of interest. Those methods have approximately doubled the rate of genetic gain for most traits in the U.S. Holstein population. With determination of causative polymorphisms, increasing the accuracy of genomic evaluations should be possible by including those genotypes as fixed effects in the analysis models. Determination of causative polymorphisms should also yield useful information on gene function and genetic architecture of complex traits. Concordance between QTL genotype as determined by the a posteriori granddaughter design and marker genotype was determined for 30 trait-by-chromosomal segment effects that are segregating in the U.S. Holstein population; a probability of <10²⁰ was used to accept the null hypothesis that no segregating gene within the chromosomal segment was affecting the trait. Genotypes for 83 grandsires and 17,217 sons were determined by either complete sequence or imputation for 3,148,506 polymorphisms across the entire genome. Variant sites were identified from previous studies (such as the 1000 Bull Genomes Project) and from DNA sequencing of bulls unique to this project, which is one of the largest marker variant surveys conducted for the Holstein breed of cattle. Effects for stature on chromosome 11, daughter pregnancy rate on chromosome 18, and protein percentage on chromosome 20 met 3 criteria: (1) complete or nearly complete concordance, (2) nominal significance of the polymorphism effect after correction for all other polymorphisms, and (3) marker coefficient of determination >40% of total multiple-regression coefficient of determination for the 30 polymorphisms with highest concordance. The missense polymorphism Phe279Tyr in GHR at 31,909,478 base pairs on chromosome 20 was confirmed as the causative mutation for fat and protein concentration. For effect on fat percentage, 12 additional missensepolymorphisms on chromosome 14 were found that had nearly complete concordance with the suggested causative polymorphism (missense mutation Ala232Glu in DGAT1). The markers used in routine U.S. genomic evaluations were increased from 60,000 to 80,000 by adding markers for known QTLs and markers detected in BARD and other research projects. Objectives 1 and 2 were completely accomplished, and objective 3 was partially accomplished. Because no new clear-cut causative polymorphisms were discovered, objectives 4 through 6 were not completed.
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Rodriguez Muxica, Natalia. Open configuration options Bioinformatics for Researchers in Life Sciences: Tools and Learning Resources. Inter-American Development Bank, February 2022. http://dx.doi.org/10.18235/0003982.
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The COVID-19 pandemic has shown that bioinformatics--a multidisciplinary field that combines biological knowledge with computer programming concerned with the acquisition, storage, analysis, and dissemination of biological data--has a fundamental role in scientific research strategies in all disciplines involved in fighting the virus and its variants. It aids in sequencing and annotating genomes and their observed mutations; analyzing gene and protein expression; simulation and modeling of DNA, RNA, proteins and biomolecular interactions; and mining of biological literature, among many other critical areas of research. Studies suggest that bioinformatics skills in the Latin American and Caribbean region are relatively incipient, and thus its scientific systems cannot take full advantage of the increasing availability of bioinformatic tools and data. This dataset is a catalog of bioinformatics software for researchers and professionals working in life sciences. It includes more than 300 different tools for varied uses, such as data analysis, visualization, repositories and databases, data storage services, scientific communication, marketplace and collaboration, and lab resource management. Most tools are available as web-based or desktop applications, while others are programming libraries. It also includes 10 suggested entries for other third-party repositories that could be of use.
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Dubcovsky, Jorge, Tzion Fahima, and Ann Blechl. Molecular characterization and deployment of the high-temperature adult plant stripe rust resistance gene Yr36 from wheat. United States Department of Agriculture, November 2013. http://dx.doi.org/10.32747/2013.7699860.bard.
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Stripe rust, caused by Puccinia striiformis f. sp. tritici is one of the most destructive fungal diseases of wheat. Virulent races that appeared within the last decade caused drastic cuts in yields. The incorporation of genetic resistance against this pathogen is the most cost-effective and environmentally friendly solution to this problem. However, race specific seedling resistance genes provide only a temporary solution because fungal populations rapidly evolve to overcome this type of resistance. In contrast, high temperature adult plant (HTAP) resistance genes provide a broad spectrum resistance that is partial and more durable. The cloning of the first wheat HTAP stripe rust resistance gene Yr36 (Science 2009, 323:1357), funded by our previous (2007-2010) BARD grant, provided us for the first time with an entry point for understanding the mechanism of broad spectrum resistance. Two paralogous copies of this gene are tightly linked at the Yr36 locus (WKS1 and WKS2). The main objectives of the current study were to characterize the Yr36 (WKS) resistance mechanism and to identify and characterize alternative WKSgenes in wheat and wild relatives. We report here that the protein coded by Yr36, designated WKS1, that has a novel architecture with a functional kinase and a lipid binding START domain, is localized to chloroplast. Our results suggest that the presence of the START domain may affect the kinase activity. We have found that the WKS1 was over-expressed on leaf necrosis in wheat transgenic plants. When the isolated WKS1.1 splice variant transcript was transformed into susceptible wheat it conferred resistance to stripe rust, but the truncated variant WKS1.2 did not confer resistance. WKS1.1 and WKS1.2 showed different lipid binding profiling. WKS1.1 enters the chloroplast membrane, while WKS1.2 is only attached outside of the chloroplast membrane. The ascorbate peroxidase (APX) activity of the recombinant protein of TmtAPXwas found to be reduced by WKS1.1 protein in vitro. The WKS1.1 mature protein in the chloroplast is able to phosphorylate TmtAPXprotein in vivo. WKS1.1 induced cell death by suppressing APX activity and reducing the ability of the cell to detoxify reactive oxygen. The decrease of APX activity reduces the ability of the plant to detoxify the reactive H2O2 and is the possible mechanism underlying the accelerated cell death observed in the transgenic plants overexpressing WKS1.1 and in the regions surrounding a stripe rust infection in the wheat plants carrying the natural WKS1.1 gene. WKS2 is a nonfunctional paralog of WKS1 in wild emmer wheat, probably due to a retrotransposon insertion close to the alternative splicing site. In some other wild relatives of wheat, such as Aegilops comosa, there is only one copy of this gene, highly similar to WKS2, which is lucking the retrotransposon insertion. WKS2 gene present in wheat and WKS2-Ae from A. showed a different pattern of alternative splice variants, regardless of the presence of the retrotransposon insertion. Susceptible Bobwhite transformed with WKS2-Ae (without retrotansposon insertion in intron10), which derived from Aegilops comosaconferred resistance to stripe rust in wheat. The expression of WKS2-Ae in transgenic plants is up-regulated by temperature and pathogen infection. Combination of WKS1 and WKS2-Ae shows improved stripe rust resistance in WKS1×WKS2-Ae F1 hybrid plants. The obtained results show that WKS1 protein is accelerating programmed cell death observed in the regions surrounding a stripe rust infection in the wheat plants carrying the natural or transgenic WKS1 gene. Furthermore, characterization of the epistatic interactions of Yr36 and Yr18 demonstrated that these two genes have additive effects and can therefore be combined to increase partial resistance to this devastating pathogen of wheat. These achievements may have a broad impact on wheat breeding efforts attempting to protect wheat yields against one of the most devastating wheat pathogen.
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Chamovitz, Daniel A., and Albrecht G. Von Arnim. eIF3 Complexes and the eIF3e Subunit in Arabidopsis Development and Translation Initiation. United States Department of Agriculture, September 2009. http://dx.doi.org/10.32747/2009.7696545.bard.
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The original working hypothesis of our proposal was that The “e” subunit of eIF3 has multiple functions from both within the nucleus and in the cytoplasm. Within this model, we further hypothesized that the “e” subunit of eIF3 functions in translation as a repressor. We proposed to test these hypotheses along the following specific aims: 1) Determine the subcellular localization of the interaction between eIF3e and other eIF3 subunits, or the COP9 signalosome. 2) Elucidate the biological significance of the varied subcellular localizations of eIF3e through generating Arabidopsis eIF3e alleles with altered subcellular localization. 3.) Purify different eIF3e complexes by tandem affinity purification (TAP). 4) Study the role of eIF3e in translational repression using both in vitro and in planta assays. eIF3 is an evolutionarily ancient and essential component of the translational apparatus in both the plant and animal kingdoms. eIF3 is the largest, and in some ways the most mysterious, of the translation factors. It is a multi-subunit protein complex that has a structural/scaffolding role in translation initiation. However, despite years of study, only recently have differential roles for eIF3 in the developmental regulation of translation been experimentally grounded. Furthermore, the roles of individual eIF3 subunits are not clear, and indeed some, such as the “e” subunit may have roles independent of translation initiation. The original three goals of the proposal were technically hampered by a finding that became evident during the course of the research – Any attempt to make transgenic plants that expressed eIF3e wt or eIF3e variants resulted in seedling lethality or seed inviability. That is, it was impossible to regenerate any transgenic plants that expressed eIF3e. We did manage to generate plants that expressed an inducible form of eIF3e. This also eventually led to lethality, but was very useful in elucidating the 4th goal of the research (Yahalom et al., 2008), where we showed, for the first time in any organism, that eIF3e has a repressory role in translation. In attempt to solve the expression problems, we also tried expression from the native promoter, and as such analyzed this promoter in transgenic plants (Epel, 2008). As such, several additional avenues were pursued. 1) We investigated protein-protein interactions of eIF3e (Paz-Aviram et al., 2008). 2) The results from goal #4 led to a novel hypothesis that the interaction of eIF3e and the CSN meets at the control of protein degradation of nascent proteins. In other words, that the block in translation seen in csn and eIF3e-overexpressing plants (Yahalom et al., 2008) leads to proteasome stress. Indeed we showed that both over expression of eIF3e and the csn mutants lead to the unfolded protein response. 3) We further investigated the role of an additional eIF3 subunit, eIF3h, in transalational regulation in the apical meristem (Zhou et al., 2009). Epel, A. (2008). Characterization of eIF3e in the model plant Arabidopsis thaliana. In Plant Sciences (Tel Aviv, Tel Aviv University). Paz-Aviram, T., Yahalom, A., and Chamovitz, D.A. (2008). Arabidopsis eIF3e interacts with subunits of the ribosome, Cop9 signalosome and proteasome. Plant Signaling and Behaviour 3, 409-411. Yahalom, A., Kim, T.H., Roy, B., Singer, R., von Arnim, A.G., and Chamovitz, D.A. (2008). Arabidopsis eIF3e is regulated by the COP9 signalosome and has an impact on development and protein translation. Plant J 53, 300-311. Zhou, F., Dunlap, J.R., and von Arnim, A.G. The translation initiation factor subunit eIF3h is .1 involved in Arabidopsis shoot apical meristem maintenance and auxin response. (submitted to Development).
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Sordillo, Lorraine, Don Wojchowski, Gary Perdew, Arthur Saran, and Gabriel Leitner. Identification of Staphylococcus aureaus Virulence Factors Associated with Bovine Mastitis. United States Department of Agriculture, February 2001. http://dx.doi.org/10.32747/2001.7574340.bard.
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Staphylococcus aureus is a major cause of mastitis in dairy cattle. The organism is able to adhere to and penetrate mammary epithelium, forming deep seated abscesses that result in chronic infections. This study was based on the observation that certain genotypes of S. aureus are isolated more frequently from field cases of bovine mastitis than others and the most prevalent genotypes of S. aureus have an increased ability to resist neutrophil phagocytosis and killing compared to the rare variants. It was hypothesized that these predominating genotypes differentially express virulence factors that allow them to overcome or suppress essential host defense mechanisms and successfully colonize mammary parenchyma. The overall objective of this study was to determine the mechanisms by which predominating S. aureus genotypes were able to resist mammary gland defense mechanisms. The following specific aims were accomplished to address the overall objectives of this project: 1. Analyze and compare cell surface and secreted protein profiles of common and rare S. aureus genotypes isolated from field cases of bovine mastitis. 2. Purify and sequence selectively synthesized proteins unique to the most prevalent genotypes of S. aureus . 3. Determine the in vitro effects of isolated proteins on essential host defense mechanisms. Results from each specific aim showed that these redominating genotypes differentially express factors that may allow them to overcome or suppress essential host defense mechanisms and successfully colonize mammary parenchyma. Using complementary approaches, both the US and Israeli teams identified differentially expressed S. aureus factors that were positively correlated with virulence as determined by the ability to modify host immune cell responses and increase disease pathogenesis. Several candidate virulence factors have ben identified at both the molecular (US team) and protein (Israeli team) levels. Components of the phosphotransferase system were shown to be differentially expressed in prevalent strains of S. aureus and to modify the growth potential of these strains in a milk microenvironment. Evidence provided by both the Israeli and US teams also demonstrated a potential role of Staphylococcal enterotoxins in the pathogenesis of mastitis. Certain enterotoxins were shown to directly affect neutrophil bactericidal activities which can profoundly affect the establishment of new intramammary infections. Other evidence suggests that S. aureus superantigens can suppress mammary defenses by enhancing lymphoid suppressor cell activity. Collectively, these data suggest that unique factors are associated with predominating S. aureus genotypes that can affect in vitro and in vivo virulence as related to the pathogenesis of bovine mastitis. The potential development of a subunit mastitis vaccine which incorporates only relevant antigenic determinants has not been investigated in depth. Experiments outlined in this proposal has identified putative virulence factors which contribute to the pathogenesis of S. aureus mastitis and which may be used to formulate an efficacious subunit mastitis vaccine. Results from these studies may lead to the development of new methods to prevent this costly disease, providing a viable alternative to less effective mastitis control procedures based on chemotherapy.
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Gelb, Jr., Jack, Yoram Weisman, Brian Ladman, and Rosie Meir. Identification of Avian Infectious Brochitis Virus Variant Serotypes and Subtypes by PCR Product Cycle Sequencing for the Rational Selection of Effective Vaccines. United States Department of Agriculture, December 2003. http://dx.doi.org/10.32747/2003.7586470.bard.
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Objectives 1. Determine the serotypic identities of 40 recent IBV isolates from commercial chickens raised in the USA and Israel. 2. Sequence all IBV field isolates using PCR product cycle sequencing and analyze their S 1 sequence to detennine their homology to other strains in the Genbank and EMBL databases. 3. Select vaccinal strains with the highest S 1 sequence homology to the field isolates and perform challenge of immunity studies in chickens in laboratory trials to detennine level of protection afforded by the vaccines. Background Infectious bronchitis (IB) is a common, economically important disease of the chicken. IB occurs as a respiratory form, associated with airsacculitis, condemnation, and mortality of meat-type broilers, a reproductive form responsible for egg production losses in layers and breeders, and a renal form causing high mortality in broilers and pullets. The causative agent is avian coronavirus infectious bronchitis virus (IBV). Replication of the virus' RNA genome is error-prone and mutations commonly result. A major target for mutation is the gene encoding the spike (S) envelope protein used by the virus to attach and infect the host cell. Mutations in the S gene result in antigenic changes that can lead to the emergence of variant serotypes. The S gene is able to tolerate numerous mutations without compromising the virus' ability to replicate and cause disease. An end result of the virus' "flexibility" is that many strains of IBV are capable of existing in nature. Once formed, new mutant strains, often referred to as variants, are soon subjected to immunological selection so that only the most antigenically novel variants survive in poultry populations. Many novel antigenic variant serotypes and genotypes have been isolated from commercial poultry flocks. Identification of the field isolates of IBV responsible for outbreaks is critical for selecting the appropriate strain(s) for vaccination. Reverse transcriptase polymerase chain reaction (RT-PCR) of the Sl subunit of the envelope spike glycoprotein gene has been a common method used to identify field strains, replacing other time-consuming or less precise tests. Two PCR approaches have been used for identification, restriction fragment length polymorphism (RFLP) and direct automated cycle sequence analysis of a diagnostically relevant hypervariab1e region were compared in our BARD research. Vaccination for IB, although practiced routinely in commercial flocks, is often not protective. Field isolates responsible for outbreaks may be unrelated to the strain(s) used in the vaccination program. However, vaccines may provide varying degrees of cross- protection vs. unrelated field strains so vaccination studies should be performed. Conclusions RFLP and S1 sequence analysis methods were successfully performed using the field isolates from the USA and Israel. Importantly, the S1 sequence analysis method enabled a direct comparison of the genotypes of the field strains by aligning them to sequences in public databases e.g. GenBank. Novel S1 gene sequences were identified in both USA and Israel IBVs but greater diversity was observed in the field isolates from the USA. One novel genotype, characterized in this project, Israel/720/99, is currently being considered for development as an inactivated vaccine. Vaccination with IBV strains in the US (Massachusetts, Arkansas, Delaware 072) or in Israel (Massachusetts, Holland strain) provided higher degrees of cross-protection vs. homologous than heterologous strain challenge. In many cases however, vaccination with two strains (only studies with US strains) produced reasonable cross-protection against heterologous field isolate challenge. Implications S1 sequence analysis provides numerical similarity values and phylogenetic information that can be useful, although by no means conclusive, in developing vaccine control strategies. Identification of many novel S1 genotypes of IBV in the USA is evidence that commercial flocks will be challenged today and in the future with strains unrelated to vaccines. In Israel, monitoring flocks for novel IBV field isolates should continue given the identification of Israel/720/99, and perhaps others in the future. Strains selected for vaccination of commercial flocks should induce cross- protection against unrelated genotypes. Using diverse genotypes for vaccination may result in immunity against unrelated field strains.
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Augustoni, Arnold L. Laser hazard analysis for airborne AURA (Big Sky variant) Proteus platform. Office of Scientific and Technical Information (OSTI), February 2004. http://dx.doi.org/10.2172/918320.
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Kulesz-Martin, Molly. The Tumor Suppressor Protein p53 and its Physiological Splicing Variant p53as in a Mouse Mammary Cancer Model. Fort Belvoir, VA: Defense Technical Information Center, October 1997. http://dx.doi.org/10.21236/ada340579.
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