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Tang, Ziyang. „A Study on the Relationship between the 3-D Structure of Spike Proteins and Infectiousness of SARS-CoV-2 Delta Variant“. Highlights in Science, Engineering and Technology 8 (17.08.2022): 169–77. http://dx.doi.org/10.54097/hset.v8i.1124.
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Since the outbreak of novel coronavirus pneumonia in Wuhan in 2019, the SARS-CoV-2 epidemic has become a hot topic. Over time, SARS-CoV-2 has evolved many variants. The diversity of the 3-D structure of the variant’s proteins resulted in the difference in the binding ability and infectious differences between different virus variants and human angiotensin-converting enzyme 2 (ACE2) receptors. In 2020, an evolutionary analysis of the Delta and Delta Plus variants of SARS-CoV-2 provided a three-dimensional model of the protein of the delta variant. However, it only focused on the delta variant and Delta plus variant themselves and did not compare the delta variant or delta plus variant with the original strain. It is hard to give a direct or apparent reason why the delta variant is more infectious and difficult to cure than the original strain. Therefore, this paper further compared the 3-D structures of homologous trimeric spike glycoproteins (S-proteins) and the receptor-binding domain between the SARS-COV-2 original strain and the SARS-COV-2 delta variant. By observing and analyzing the models of the above proteins in the PyMOL Molecular Graphics System, the reasons for the increase of infectivity of the delta variant can be interpreted in a direct way. This article also focuses on the data of the Indian cases from the JHU database to deeply analyze the relationship between the structure and transmission ability of the SARS-CoV-2 delta variant. Last but not least, the reproductive ability of SARS-CoV-2 can be reflected by the number of NAG (2-acetamido-2-deoxy-beta-D-glucopyranose). Through data analysis and protein structure research, we can better understand the characteristics of the binding of SARS-CoV-2 to the human receptor, thus providing a theoretical basis for accurately predicting virus variation. Through the comparative study of virus structure and infectiousness, this paper will provide a scientific basis for the relevant departments to improve epidemic prevention and improve the public's vigilance against virus variants.
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Parasonis, J., und G. Ambrasas. „AN ANALYSIS OF FACTORS FOR THE SELECTION OF A TECHNICAL SOLUTION VERSION IN THERMAL RENOVATION OF BUILDINGS/ŠILUMINĖS RENOVACIJOS TECHNINIO SPRENDIMO VARIANTO PASIRINKIMO VEIKSNIŲ ANALIZĖ“. JOURNAL OF CIVIL ENGINEERING AND MANAGEMENT 1, Nr. 4 (31.12.1995): 67–74. http://dx.doi.org/10.3846/13921525.1995.10531534.
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Susistemintai nagrinėjamas šiluminės renovacijos techninio sprendimo varianto parinkimas. Renovacijos procesas analizuojamas keturiose stadijose: tikslų-projektavimo-statybos-eksploatacijos. Šiluminės renovacijos varianto pasirinkimą įtakoja daugelis veiksnių. Straipsnyje nagrinėjama veiksnių įtaka tiek atskirai stadijai, tiek visam renovacijos procesui. Atkreipiamas dėmesys į priešprojektinės diagnostikos svarbą teisingai įvertinant pastato būklę, galimus sprendimų apribojimus ir formuojant renovacijos techninio sprendimo alternatyvius variantus. Kalbama apie skirtingų konstruktyvinių sprendimų privalumus ir trūkumus, įtakojančius pasirinkimą. Atkreipiamas dėmesys į tai, kad, atlikus šiluminę renovaciją, gali tekti tvarkyti inžinerinę pastato įrangą. Pažymima kokybinių rodiklių, pvz., estetiškumo ir komfortabilumo, siekimo įtaka parenkant variantą. Aptariamas susistemintas požiūris į techninio sprendimo varianto pasirinkimą pateikiamas algoritmine forma. Pasirinkta metodika, kuomet investicinis procesas nagrinėjamas nuosekliai pagal tikslų-projektavimo-statybos-eksploatacijos stadijas, leidžia daryti prielaidą, jog tokiu būdu pavyksta įvertinti daugelį sprendimo priėmimą. įtakojančių veiksnių.
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Iqbal, Sumaiya, David Hoksza, Eduardo Pérez-Palma, Patrick May, Jakob B. Jespersen, Shehab S. Ahmed, Zaara T. Rifat et al. „MISCAST: MIssense variant to protein StruCture Analysis web SuiTe“. Nucleic Acids Research 48, W1 (13.05.2020): W132—W139. http://dx.doi.org/10.1093/nar/gkaa361.
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Abstract Human genome sequencing efforts have greatly expanded, and a plethora of missense variants identified both in patients and in the general population is now publicly accessible. Interpretation of the molecular-level effect of missense variants, however, remains challenging and requires a particular investigation of amino acid substitutions in the context of protein structure and function. Answers to questions like ‘Is a variant perturbing a site involved in key macromolecular interactions and/or cellular signaling?’, or ‘Is a variant changing an amino acid located at the protein core or part of a cluster of known pathogenic mutations in 3D?’ are crucial. Motivated by these needs, we developed MISCAST (missense variant to protein structure analysis web suite; http://miscast.broadinstitute.org/). MISCAST is an interactive and user-friendly web server to visualize and analyze missense variants in protein sequence and structure space. Additionally, a comprehensive set of protein structural and functional features have been aggregated in MISCAST from multiple databases, and displayed on structures alongside the variants to provide users with the biological context of the variant location in an integrated platform. We further made the annotated data and protein structures readily downloadable from MISCAST to foster advanced offline analysis of missense variants by a wide biological community.
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Zavadskas, Edmundas K., Artūras Kaklauskas und Zenonas Turskis. „MULTICRITERIA DECISION-MAKING SYSTEM FOR BUILDING REFURBISHMENT/PASTATŲ ATNAUJINIMO DAUGIAKRITERINĖ SPRENDIMŲ PRIĖMIMO SISTEMA“. JOURNAL OF CIVIL ENGINEERING AND MANAGEMENT 3, Nr. 12 (31.12.1997): 62–68. http://dx.doi.org/10.3846/13921525.1997.10531368.
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Šiame straipsnyje pastatų atnaujinimas suprantamas kaip statybinė veikla, kurios tikslas pertvarkyti esamą statinį, siekiant pašalinti jo fizinį, ekonominį, inžinerinės įrangos, teisinį, architektūrinį-estetinį, funkcinį, komfortinį, eksploatacinį, socialinį ir kitokį nusidėvėjimą. Į pastatų atnaujinimo poreikį galima žiūrėti kaip į skirtumą tarp esamos pastato padėties ir norimos. Pastatų atnaujinimą galima atlikti naudojant alternatyvias medžiagas, konstrukcijas, inžinerinę įrangą, technologijas ir pan. Pagal naudojamų sprendimų variantus keičiasi atnaujinamo pastato efektyvumas. Sprendimų variantiškumas leidžia racionaliau ir realiau įvertinti ekonomines, klimato, teisines, socialines sąlygas, tradicijas; atpiginti projektą; geriau tenkinti architektūrinius, komfortinius, funkcinius, eksploatacinius ir kitus užsakovo poreikius. Atnaujinimas gali būti minimalus (dalinio fizinio pastato nusidėvėjimo (stogeliai, balkonai, karnizai, siūlės) pašalinimas), maksimalus (kai visi nusidėvėjimai pašalinami) arba kuris nors tarpinis variantas (dalinė ar kompleksinė šiluminė renovacija, šildymo sistemos reguliavimo ir apskaitos diegimas, racionalus normatyvų bazės paruošimas ir t.t.). Pastato atnaujinimo varianto parinkimas daugiausia priklauso nuo gyventojų poreikių ir esamų finansinių galimybių. Siekiant nustatyti efektyvų atnaujinimo variantą, buvo sukurta pastatų atnaujinimo daugiakriterinė sprendimų priėmimų sistema, susidedanti is žinių bazės ir sprendimų priėmimo posistemio. Žinių bazėje kaupiama įvairi informacija, sudaranti sąlygas sprendimų priėmimų posistemiui efektyviai atlikti pastatų atnaujinimo variantinį projektavimą bei daugiakriterinę analizę. Žinių bazė susideda iš tokių dalių: pradinių duomenų žinių lentelių; atnaujinimo įvertinimo žinių lentelių, t.y. lentelių, kuriose pateikiama informacija apie alternatyvius atnaujinimo variantus (pastatų elementų, inžinerinės įrangos ir pan.); variantinio projektavimo žinių lentelių, t.y. lentelių, kuriose pateikiama informacija apie galimas alternatyvių atnaujinimo sprendimų tarpusavio derinių kombinacijas; grafinės dalies žinių lentelių, kuriose pateikiama grafinė atnaujinimo variantus apibūdinanti informacija; žinių lentelių užpildymo rekomendacijų. Sprendimų priėmimo posistemyje yra užprogramuoti tokie autorių pasiūlyti metodai: projektų variantinio projektavimo; kriterijų reikšmingumo nustatymo; projektų sistemotechninės analizės; projektų naudingumo laipsnio ir sutartinės kainos nustatymo. Skaičiavimo metu kartu su pradiniais duomenimis ESM atmintyje iš žinių bazės kaupiama informacija, tiesiogiai susijusi su sprendžiama problema. Tokiu būdu ESM atmintyje suformuojama visa nagrinėjamas alternatyvas išsamiai apibūdinanti informacija. Išanalizavus visą šią informaciją ir jos tarpusavio ryšius bei atlikus daugelį veiksmų, sprendimų priėmimų posistemis suformuoja galimus pastatų atnaujinimo variantus. Po to šis posistemis, remdamasis užsakovo pateiktais pradiniais duomenimis (esamos finansinės galimybės, norimas atnaujinimo lygis ir pan.), išrenka efektyviausią alternatyvą.
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Rychen, Jonathan, Daniel W. Zumofen, Howard A. Riina, Luigi Mariani und Raphael Guzman. „The Transpalpebral Versus the Transciliary Variant of the Supraorbital Keyhole Approach: Anatomic Concepts for Aneurysm Surgery“. Operative Neurosurgery 19, Nr. 1 (12.12.2019): E24—E31. http://dx.doi.org/10.1093/ons/opz358.
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Abstract BACKGROUND The supraorbital craniotomy (SOC) is classically performed through a skin incision in the patient's eyebrow. A variant with a skin incision in the patient's eyelid has become increasingly popular in recent years. OBJECTIVE To compare the transpalpebral and the transciliary variants of the SOC with regard to their potential role in aneurysm surgery. METHODS We carried out cadaveric dissections and virtual craniotomies on computerized tomography datasets. The skin incision, the craniotomy location and size, the working angles, and the achievable exposure of neurovascular structures were assessed and compared for both variants of the SOC. RESULTS The skin incision measured 4 cm for the transpalpebral and 3 cm for the transciliary variant. The skin could be retracted 1.5 cm upward from the lower edge of the orbital rim with the transpalpebral and 2.5 cm upward with the transciliary variant. The craniotomy size was 2.5 × 1.5 cm for both variants, given that the transpalpebral variant included an orbital osteotomy. The bony opening in the transpalpebral variant was 1 cm more caudal; this restricted the craniocaudal working angles and, thereby, limited the achievable exposure of neurovascular structures in the paraclinoid area and along the sphenoid ridge. CONCLUSION If the orbital rim and the anterior aspect of the orbital roof are removed, then the transpalpebral variant of the SOC enables a bony opening that is just as large as that of the transciliary variant. Nonetheless, the more caudal location of the bony opening alters the available working angles and may impede exposure of key structures during aneurysm surgery.
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Glavaški, Mila, Aleksandra Ilić und Lazar Velicki. „Gene-Specific Discriminative Echocardiogram Findings in Hypertrophic Cardiomyopathy Determined Using Artificial Intelligence: A Pilot Study“. Cardiogenetics 14, Nr. 1 (25.12.2023): 1–25. http://dx.doi.org/10.3390/cardiogenetics14010001.
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Hypertrophic cardiomyopathy (HCM) is among the most common forms of cardiomyopathies, with a prevalence of 1:200 to 1:500 people. HCM is caused by variants in genes encoding cardiac sarcomeric proteins, of which a majority reside in MYH7, MYBPC3, and TNNT2. Up to 40% of the HCM cases do not have any known HCM variant. Genotype–phenotype associations in HCM remain incompletely understood. This study involved two visits of 46 adult patients with a confirmed diagnosis of HCM. In total, 174 genes were analyzed on the Next-Generation Sequencing platform, and transthoracic echocardiography was performed. Gene-specific discriminative echocardiogram findings were identified using the computer vision library Fast AI. This was accomplished with the generation of deep learning models for the classification of ultrasonic images based on the underlying genotype and a later analysis of the most decisive image regions. Gene-specific echocardiogram findings were identified: for variants in the MYH7 gene (vs. variant not detected), the most discriminative structures were the septum, left ventricular outflow tract (LVOT) segment, anterior wall, apex, right ventricle, and mitral apparatus; for variants in MYBPC3 gene (vs. variant not detected) these were the septum, left ventricle, and left ventricle/chamber; while for variants in the TNNT2 gene (vs. variant not detected), the most discriminative structures were the septum and right ventricle.
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Hefer, Tsila, Henry Z. Joachims, Arie Eitan und Mariana Munichor. „Are the morphology of papillary thyroid carcinoma and the tumour's behaviour correlated?“ Journal of Laryngology & Otology 110, Nr. 7 (Juli 1996): 704–5. http://dx.doi.org/10.1017/s0022215100134693.
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AbstractSix cases of papillary thyroid carcinoma showing clinically highly aggressive behaviour by invading the upper airway and digestive tract structures were retrospectively reviewed to evaluate the morphological variants of the tumours. Four of them were found to be pure papillary and one was a mixed-papillary and follicular-variants regarded as non-aggressive. Only one case was found to be tall cell variant – regarded as an aggressive variant of papillary thyroid carcinoma. The findings suggest that the prognosis of papillary thyroid carcinoma cannot be predicted from its morphological variant and attention should be given to other clinical parameters.
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Treuheit, M. J., C. E. Costello und H. B. Halsall. „Analysis of the five glycosylation sites of human α1-acid glycoprotein“. Biochemical Journal 283, Nr. 1 (01.04.1992): 105–12. http://dx.doi.org/10.1042/bj2830105.
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Orosomucoid (OMD) contains complex bi-, tri- and tetra-antennary glycan chains. Subfractionation of OMD into three molecular variants using concanavalin A lectin chromatography is based on variations in these complex structures. Standard h.p.l.c. profiles have been developed to analyse the percentage and distribution of the glycoforms present at each glycosylation site in OMD and its molecular variants. The ability to quantify the glycoforms present at each site allows us to extend the earlier results of others and resolve the remaining questions concerning the glycan structures of these variants. Most significantly, the proportions of bi-, tri- and tetra-antennary chains differ at each site for the three molecular variants. The most strongly retained variant from concanavalin A is uniquely capable of possessing biantennary chains at all five sites, whereas the unretained variant is completely devoid of biantennary chains. Only glycosylation site II of the five present is 100% biantennary in the retained and weakly retained variants. In addition, the two gene products of OMD were differentially glycosylated. Molecular masses of the glycoforms were verified by matrix-assisted u.v. laser desorption mass spectrometry. On the basis of the site distribution of oligosaccharides in the variants, efforts were made to understand the factors that control the processing of the carbohydrate chains in OMD. The results indicate that the ‘site-directed’ model of processing offers the most consistent explanation for the structures seen at the individual glycosylation sites of OMD.
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Möller, Steffen, Eilhard Mix, Martin Blüggel, Pablo Serrano-Fernández, Dirk Koczan, Vasilis Kotsikoris, Manfred Kunz et al. „Collection of Soluble Variants of Membrane Proteins for Transcriptomics and Proteomics“. In Silico Biology: Journal of Biological Systems Modeling and Multi-Scale Simulation 5, Nr. 3 (Januar 2005): 295–311. https://doi.org/10.3233/isb-00188.
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The existence of a soluble splice variant for a gene encoding a transmembrane protein suggests that this gene plays a role in intercellular signalling, particularly in immunological processes. Also, the absence of a splice variant of a reported soluble variant suggests exclusive control of the solubilisation by proteolytic cleavage. Soluble splice variants of membrane proteins may also be interesting targets for crystallisation as their structure may be expected to preserve, at least partially, their function as integral membrane proteins, whose structures are most difficult to determine. This paper presents a dataset derived from the literature in an attempt to collect all reported soluble variants of membrane proteins, be they splice variants or shedded. A list of soluble variants is derived in silico from Ensembl. These are checked on their presence in multiple organisms and their number of membranespanning regions is inspected. The findings then are confirmed by a comparison with identified proteins of a recent global proteomics study of human blood plasma. Finally, a tool to support the identification of novel soluble variants by proteomics is provided.
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Delers, Francisco, Gérard Strecker und Robert Engler. „Glycosylation of chicken haptoglobin: Isolation and characterization of three molecular variants and studies of their distribution in hen plasma before and after turpentine-induced inflammation“. Biochemistry and Cell Biology 66, Nr. 3 (01.03.1988): 208–17. http://dx.doi.org/10.1139/o88-028.
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Chicken haptoglobin (Hp), a hemoglobin-binding protein isolated from chicken plasma, is composed of three molecular variants that react differently with concanavalin A (ConA). These glycosylation variants of chicken Hp have been isolated by affinity chromatography using Sepharose-bound ConA. They differ in their molecular weight, as determined by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. Analysis of the glycopeptides obtained after pronase digestion of these variants yielded two types of structures: one, reactive with ConA, corresponded to a biantennary N-linked carbohydrate unit and one, unreactive with ConA, corresponded to a triantennary unit. The strongly ConA-reactive Hp variant bears only two biantennary units and the nonreactive Hp variant bears only two triantennary units; the weakly reactive Hp variant bears equal amounts of both units. The distribution of Hp glycosylation variant does not show any significant difference when obtained from the plasma of laying hens before and after turpentine-induced inflammation.
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Valenzuela-Fuenzalida, Juan Jose, Fernanda Pena-Santibañez, Ayline Vergara Salinas, Trinidad Meneses Caroca, Javiera Rojo-Gonzalez, Mathias Ignacio Orellana-Donoso, Pablo Nova-Baeza, Alejandra Suazo-Santibañez, Juan Sanchis-Gimeno und Hector Gutierrez-Espinoza. „Hepatic Hilum Variations and Their Clinical Considerations in the Liver: A Systematic Review and Meta-Analysis“. Life 14, Nr. 10 (14.10.2024): 1301. http://dx.doi.org/10.3390/life14101301.
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Background: The liver has a region called the hepatic hilum (HH) where structures enter and exit: anteriorly, the left and right hepatic ducts; posteriorly, the portal vein; and between these, the left and right hepatic arteries. The objective of this review is to know how variants in structures of the hepatic hilum are associated with clinical alterations of the liver. Methods: The databases Medline, Scopus, Web of Science, Google Scholar, CINAHL, and LILACS were researched until January 2024. The methodological quality was evaluated with an assurance tool for anatomical studies (AQUA). The pooled prevalence was estimated using a random effects model. Results: A total of six studies met the selection criteria established in this study for meta-analysis. The prevalence of hepatic hilus variants was 9% (CI = 5% to 13%), and the heterogeneity was 83%. The other studies were analyzed descriptively and with their respective clinical considerations in the presence of the variant, such as the high incidence of the Michels type III variant; among the portal vein variants, the type III variant of the Cheng classification stands out and in biliary anatomy, and the IIIa variant stands out according to the Choi classification. Conclusions: This review allowed us to know in detail the anatomical variants of HH; the structure with which the greatest care should be taken is the hepatic artery because of the probability of metastatic processes due to increased blood distribution in the hepatic lobules. Finally, we believe that new anatomical and clinical studies are needed to improve our knowledge of the relationship between HH variants and liver alterations or surgeries.
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Henry, Maya L., Stephen M. Wilson, Miranda C. Babiak, Maria Luisa Mandelli, Pelagie M. Beeson, Zachary A. Miller und Maria Luisa Gorno-Tempini. „Phonological Processing in Primary Progressive Aphasia“. Journal of Cognitive Neuroscience 28, Nr. 2 (Februar 2016): 210–22. http://dx.doi.org/10.1162/jocn_a_00901.
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Individuals with primary progressive aphasia (PPA) show selective breakdown in regions within the proposed dorsal (articulatory–phonological) and ventral (lexical–semantic) pathways involved in language processing. Phonological STM impairment, which has been attributed to selective damage to dorsal pathway structures, is considered to be a distinctive feature of the logopenic variant of PPA. By contrast, phonological abilities are considered to be relatively spared in the semantic variant and are largely unexplored in the nonfluent/agrammatic variant. Comprehensive assessment of phonological ability in the three variants of PPA has not been undertaken. We investigated phonological processing skills in a group of participants with PPA as well as healthy controls, with the goal of identifying whether patterns of performance support the dorsal versus ventral functional–anatomical framework and to discern whether phonological ability differs among PPA subtypes. We also explored the neural bases of phonological performance using voxel-based morphometry. Phonological performance was impaired in patients with damage to dorsal pathway structures (nonfluent/agrammatic and logopenic variants), with logopenic participants demonstrating particular difficulty on tasks involving nonwords. Binary logistic regression revealed that select phonological tasks predicted diagnostic group membership in the less fluent variants of PPA with a high degree of accuracy, particularly in conjunction with a motor speech measure. Brain–behavior correlations indicated a significant association between the integrity of gray matter in frontal and temporoparietal regions of the left hemisphere and phonological skill. Findings confirm the critical role of dorsal stream structures in phonological processing and demonstrate unique patterns of impaired phonological processing in logopenic and nonfluent/agrammatic variants of PPA.
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Abell, Nathan S., Marianne K. DeGorter, Michael J. Gloudemans, Emily Greenwald, Kevin S. Smith, Zihuai He und Stephen B. Montgomery. „Multiple causal variants underlie genetic associations in humans“. Science 375, Nr. 6586 (18.03.2022): 1247–54. http://dx.doi.org/10.1126/science.abj5117.
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Associations between genetic variation and traits are often in noncoding regions with strong linkage disequilibrium (LD), where a single causal variant is assumed to underlie the association. We applied a massively parallel reporter assay (MPRA) to functionally evaluate genetic variants in high, local LD for independent cis-expression quantitative trait loci (eQTL). We found that 17.7% of eQTLs exhibit more than one major allelic effect in tight LD. The detected regulatory variants were highly and specifically enriched for activating chromatin structures and allelic transcription factor binding. Integration of MPRA profiles with eQTL/complex trait colocalizations across 114 human traits and diseases identified causal variant sets demonstrating how genetic association signals can manifest through multiple, tightly linked causal variants.
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Yin, Xuemin, Dong Zeng, Yingjun Liao, Chengyuan Tang und Ying Li. „The Function of H2A Histone Variants and Their Roles in Diseases“. Biomolecules 14, Nr. 8 (12.08.2024): 993. http://dx.doi.org/10.3390/biom14080993.
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Epigenetic regulation, which is characterized by reversible and heritable genetic alterations without changing DNA sequences, has recently been increasingly studied in diseases. Histone variant regulation is an essential component of epigenetic regulation. The substitution of canonical histones by histone variants profoundly alters the local chromatin structure and modulates DNA accessibility to regulatory factors, thereby exerting a pivotal influence on gene regulation and DNA damage repair. Histone H2A variants, mainly including H2A.Z, H2A.B, macroH2A, and H2A.X, are the most abundant identified variants among all histone variants with the greatest sequence diversity. Harboring varied chromatin occupancy and structures, histone H2A variants perform distinct functions in gene transcription and DNA damage repair. They are implicated in multiple pathophysiological mechanisms and the emergence of different illnesses. Cancer, embryonic development abnormalities, neurological diseases, metabolic diseases, and heart diseases have all been linked to histone H2A variant alterations. This review focuses on the functions of H2A histone variants in mammals, including H2A.Z, H2A.B, macroH2A, and H2A.X, and their current roles in various diseases.
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Zhou, Hong-Lu, Li-Na Chen, Song-Mei Wang, Ming Tan, Chao Qiu, Tian-Yi Qiu und Xuan-Yi Wang. „Prevalence and Evolution of Noroviruses between 1966 and 2019, Implications for Vaccine Design“. Pathogens 10, Nr. 8 (11.08.2021): 1012. http://dx.doi.org/10.3390/pathogens10081012.
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Noroviruses (NoVs), a group of single-stranded RNA viruses causing epidemic acute gastroenteritis in humans, are highly diverse, consisting of multiple genogroups with >30 genotypes. Their continual evolutions make NoV vaccine design and development difficult. Here, we report a study of NoV sequences obtained from a population-based diarrhea surveillance in Zhengding County of Hebei Province spanning from 2001 to 2019 and those available in the GenBank database from 1966 to 2019. NoV genotypes and/or variants that may evade immunity were screened and identified based on primary and conformational structures for vaccine design. We selected 366, 301, 139, 74 and 495 complete VP1-coding nucleotide sequences representing the predominant genotypes of GII.4, GII.2, GII.3, GII.6 and GII.17, respectively. A total of 16 distinct GII.4 variants were identified, showing a typical linear evolutionary pattern of variant replacement, while only 1–4 variants of the other genotypes were found to co-circulate over the 40–50-year period without typical variant replacement. The vaccine strain GII.4c is close to variant Sydney_2012 (0.053) in their primary structure, but they are distinct at epitopes A and E in conformations. Our data suggested GII.4 variant Sydney_2012, GII.2 variant A, a GII.3 strain, GII.6 variants B and C and GII.17 variant D are primary candidate strains for NoV vaccine development.
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Melters, Daniël P., Mary Pitman, Tatini Rakshit, Emilios K. Dimitriadis, Minh Bui, Garegin A. Papoian und Yamini Dalal. „Intrinsic elasticity of nucleosomes is encoded by histone variants and calibrated by their binding partners“. Proceedings of the National Academy of Sciences 116, Nr. 48 (11.11.2019): 24066–74. http://dx.doi.org/10.1073/pnas.1911880116.
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Histone variants fine-tune transcription, replication, DNA damage repair, and faithful chromosome segregation. Whether and how nucleosome variants encode unique mechanical properties to their cognate chromatin structures remains elusive. Here, using in silico and in vitro nanoindentation methods, extending to in vivo dissections, we report that histone variant nucleosomes are intrinsically more elastic than their canonical counterparts. Furthermore, binding proteins, which discriminate between histone variant nucleosomes, suppress this innate elasticity and also compact chromatin. Interestingly, when we overexpress the binding proteins in vivo, we also observe increased compaction of chromatin enriched for histone variant nucleosomes, correlating with diminished access. Taken together, these data suggest a plausible link between innate mechanical properties possessed by histone variant nucleosomes, the adaptability of chromatin states in vivo, and the epigenetic plasticity of the underlying locus.
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Weinberg, Zasha, James W. Nelson, Christina E. Lünse, Madeline E. Sherlock und Ronald R. Breaker. „Bioinformatic analysis of riboswitch structures uncovers variant classes with altered ligand specificity“. Proceedings of the National Academy of Sciences 114, Nr. 11 (06.03.2017): E2077—E2085. http://dx.doi.org/10.1073/pnas.1619581114.
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Riboswitches are RNAs that form complex, folded structures that selectively bind small molecules or ions. As with certain groups of protein enzymes and receptors, some riboswitch classes have evolved to change their ligand specificity. We developed a procedure to systematically analyze known riboswitch classes to find additional variants that have altered their ligand specificity. This approach uses multiple-sequence alignments, atomic-resolution structural information, and riboswitch gene associations. Among the discoveries are unique variants of the guanine riboswitch class that most tightly bind the nucleoside 2′-deoxyguanosine. In addition, we identified variants of the glycine riboswitch class that no longer recognize this amino acid, additional members of a rare flavin mononucleotide (FMN) variant class, and also variants of c-di-GMP-I and -II riboswitches that might recognize different bacterial signaling molecules. These findings further reveal the diverse molecular sensing capabilities of RNA, which highlights the potential for discovering a large number of additional natural riboswitch classes.
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W.N. RATNANINGRUM, YENI, und AFFAN KURNIAWAN. „Floral structure and genetical differences of sandalwood variants in Gunung Sewu (Java, Indonesia), and its effects on breeding systems and reproductive ability“. Biodiversitas Journal of Biological Diversity 20, Nr. 2 (21.01.2019): 393–404. http://dx.doi.org/10.13057/biodiv/d200213.
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Ratnaningrum YWN, Kurniawan A. 2019. Floral structure and genetical differences of sandalwood variants in Gunung Sewu (Java, Indonesia), and its effects on breeding systems and reproductive ability. Biodiversitas 20: 393-404. Our preliminary studies reported that the failure on rehabilitation program of sandalwood, an endangered endemic species in Indonesia, was caused by low viability and survival due to reproductive failure. New sandalwood landraces in Gunung Sewu Geopark, Java island consist of three variants (YBF, refers to "yellow big flower"; RBF, "red big flower"; and RSF, "red small flower") differed by floral structures. This study was made on three sandalwood variants grew in four landraces representing landscape zones in Gunung Sewu, from April to September 2017 flowering season. This advanced study was aimed to estimate the differences in floral structures and genetic diversity among variants, and their effects on breeding systems and reproductive ability. Floral organ measurements were made on each variant. Isoenzyme analysis was conducted to estimate the genetic diversity of each variant and in each site. Mating systems were estimated by Index of Incompatibility (ISI) and Cruden's Out Crossing Index (OCI) methods. Reproductive ability was measured by counting Pollination Effectiveness, Reproductive Success and seed viability. Results found that six loci were polymorphic in most of sites and variants, with exception for Petir and Bejiharjo sites and YBF variant. Observed heterozygosity varied with sites but was similar among variants. Some of diversity existed among both sites and variants. The OCI value scored more than 3 for all variants, indicating an outbreeding mating system. RSF showed higher OCI value compared to both RBF and YBF. Bleberan and Nglanggeran, the outcrossed and completely self-incompatible populations (ISI = 0), failed to produce selfed seeds. In such highly outcrossing, self-incompatible populations, the highest seed set was gained from intraspecific-crossed pollination. Contrastly, the inbreeding and self-compatible populations (ISI = 3 to ∞), Petir and Bejiharjo, tended to alter its matting system to be more inbreeding. Reproductive ability differed by sites but was similar among variants.
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Li, Mi, Jaroslav Srp, Michael Mareš, Alexander Wlodawer und Alla Gustchina. „Structural studies of complexes of kallikrein 4 with wild-type and mutated forms of the Kunitz-type inhibitor BbKI“. Acta Crystallographica Section D Structural Biology 77, Nr. 8 (29.07.2021): 1084–98. http://dx.doi.org/10.1107/s2059798321006483.
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Structures of BbKI, a recombinant Kunitz-type serine protease inhibitor from Bauhinia bauhinioides, complexed with human kallikrein 4 (KLK4) were determined at medium-to-high resolution in four crystal forms (space groups P3121, P6522, P21 and P61). Although the fold of the protein was virtually identical in all of the crystals, some significant differences were observed in the conformation of Arg64 of BbKI, the residue that occupies the S1 pocket in KLK4. Whereas this residue exhibited two orientations in the highest resolution structure (P3121), making either a canonical trypsin-like interaction with Asp189 of KLK4 or an alternate interaction, only a single alternate orientation was observed in the other three structures. A neighboring disulfide, Cys191–Cys220, was partially or fully broken in all KLK4 structures. Four variants of BbKI in which Arg64 was replaced by Met, Phe, Ala and Asp were expressed and crystallized, and their structures were determined in complex with KLK4. Structures of the Phe and Met variants complexed with bovine trypsin and of the Phe variant complexed with α-chymotrypsin were also determined. Although the inhibitory potency of these variant forms of BbKI was lowered by up to four orders of magnitude, only small changes were seen in the vicinity of the mutated residues. Therefore, a totality of subtle differences in KLK4–BbKI interactions within the fully extended interface in the structures of these variants might be responsible for the observed effect. Screening of the BbKI variants against a panel of serine proteases revealed an altered pattern of inhibitory specificity, which was shifted towards that of chymotrypsin-like proteases for the hydrophobic Phe and Met P1 substitutions. This work reports the first structures of plant Kunitz inhibitors with S1-family serine proteases other than trypsin, as well as new insights into the specificity of inhibition of medically relevant kallikreins.
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Lötscher, Andreas. „Die Affrikate tsch in den Varianten des Deutschen: Wortstruktur und Wortschatzstruktur“. Zeitschrift für Dialektologie und Linguistik 87, Nr. 1 (2020): 66. http://dx.doi.org/10.25162/zdl-2020-0003.
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Lin, Qinghong, Xuejun Wang, Xiaoliao Peng, Tian Han, Ling Sun, Xiaoyu Zhang und Xingtao Zhou. „A genetic investigation in five Chinese families with keratoconus“. PeerJ 12 (02.09.2024): e18037. http://dx.doi.org/10.7717/peerj.18037.
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Background This study investigated the genetic characteristics of five Chinese families with keratoconus (KC). Methods In the five families affected by KC, medical records, clinical observations, and blood samples were collected from all individuals. All KC family members (n = 20) underwent both whole exome sequencing of genomic DNA and Sanger sequencing to confirm the variants. Online software was utilized to analyze all variants, and the online server I-TASSER was employed for in silico predictions of the three-dimensional protein structures of the variants. The newly discovered variants and single nucleotide polymorphisms were further examined in 322 sporadic KC patients. Results The Pentacam tomographic composite index in those affected first-degree family members of the probands showed a pathological change. Five new variants were detected in the five probands and other affected members in their families: a heterozygous missense variant g.19043832C>T (p.Ser145Asn) in the homer scaffolding protein 3 (HOMER3) gene; a heterozygous missense variant g.99452113G>A (p.Gly483Arg) in the insulin-like growth factor 1 receptor (IGF1R) gene; a heterozygous missense variant g.55118280G>T (p.Trp843Leu) in the echinoderm microtubule-associated protein like 6 (EML6) gene; a heterozygous frameshift variant c. 1226_1227del (p.Gln410Glufs*17) in the DOP1 leucine zipper-like protein B (DOP1B) gene; and a heterozygous splice-site variant c.7776+2T>A in the neurobeachin-like protein 2 (NBEAL2) gene. These variations were predicted to be potentially pathogenic and associated with KC. Conclusion Five novel variants in HOMER3, IGF1R, EML6, DOP1B, and NBEAL2 genes were identified in this study and may be associated with the pathogenesis of KC. This study provides new information about the gene variants and their protein changes in KC patients. The findings should be explored further and could potentially be applied to the early diagnosis of KC before clinical onset.
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Köksal, Zehra, Claus Børsting, Leonor Gusmão und Vania Pereira. „SNPtotree—Resolving the Phylogeny of SNPs on Non-Recombining DNA“. Genes 14, Nr. 10 (22.09.2023): 1837. http://dx.doi.org/10.3390/genes14101837.
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Genetic variants on non-recombining DNA and the hierarchical order in which they accumulate are commonly of interest. This variant hierarchy can be established and combined with information on the population and geographic origin of the individuals carrying the variants to find population structures and infer migration patterns. Further, individuals can be assigned to the characterized populations, which is relevant in forensic genetics, genetic genealogy, and epidemiologic studies. However, there is currently no straightforward method to obtain such a variant hierarchy. Here, we introduce the software SNPtotree v1.0, which uniquely determines the hierarchical order of variants on non-recombining DNA without error-prone manual sorting. The algorithm uses pairwise variant comparisons to infer their relationships and integrates the combined information into a phylogenetic tree. Variants that have contradictory pairwise relationships or ambiguous positions in the tree are removed by the software. When benchmarked using two human Y-chromosomal massively parallel sequencing datasets, SNPtotree outperforms traditional methods in the accuracy of phylogenetic trees for sequencing data with high amounts of missing information. The phylogenetic trees of variants created using SNPtotree can be used to establish and maintain publicly available phylogeny databases to further explore genetic epidemiology and genealogy, as well as population and forensic genetics.
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Suzuki, Yuta, Eugene W. Myers und Shinichi Morishita. „Rapid and ongoing evolution of repetitive sequence structures in human centromeres“. Science Advances 6, Nr. 50 (Dezember 2020): eabd9230. http://dx.doi.org/10.1126/sciadv.abd9230.
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Our understanding of centromere sequence variation across human populations is limited by its extremely long nested repeat structures called higher-order repeats that are challenging to sequence. Here, we analyzed chromosomes 11, 17, and X using long-read sequencing data for 36 individuals from diverse populations including a Han Chinese trio and 21 Japanese. We revealed substantial structural diversity with many previously unidentified variant higher-order repeats specific to individuals characterizing rapid, haplotype-specific evolution of human centromeric arrays, while frequent single-nucleotide variants are largely conserved. We found a characteristic pattern shared among prevalent variants in human and chimpanzee. Our findings pave the way for studying sequence evolution in human and primate centromeres.
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Cannon-Albright, Lisa A., Jeff Stevens, Julio C. Facelli, Craig C. Teerlink, Kristina Allen-Brady und Neeraj Agarwal. „High-Risk Pedigree Study Identifies LRBA (rs62346982) as a Likely Predisposition Variant for Prostate Cancer“. Cancers 15, Nr. 7 (31.03.2023): 2085. http://dx.doi.org/10.3390/cancers15072085.
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There is evidence for contribution of inherited factors to prostate cancer, and more specifically to lethal prostate cancer, but few responsible genes/variants have been identified. We examined genetic sequence data for 51 affected cousin pairs who each died from prostate cancer and who were members of high-risk prostate cancer pedigrees in order to identify rare variants shared by the cousins as candidate predisposition variants. Candidate variants were tested for association with prostate cancer risk in UK Biobank data. Candidate variants were also assayed in 1195 additional sampled Utah prostate cancer cases. We used 3D protein structure prediction methods to analyze structural changes and provide insights into mechanisms of pathogenicity. Almost 4000 rare (<0.005) variants were identified as shared in the 51 affected cousin pairs. One candidate variant was also significantly associated with prostate cancer risk among the 840 variants with data in UK Biobank, in the gene LRBA (p = 3.2 × 10−5; OR = 2.09). The rare risk variant in LRBA was observed to segregate in five pedigrees. The overall predicted structures of the mutant protein do not show any significant overall changes upon mutation, but the mutated structure loses a helical structure for the two residues after the mutation. This unique analysis of closely related individuals with lethal prostate cancer, who were members of high-risk prostate cancer pedigrees, has identified a strong set of candidate predisposition variants which should be pursued in independent studies. Validation data for a subset of the candidates identified are presented, with strong evidence for a rare variant in LRBA.
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Kumar, Anil, Rajni Sharma, Mohammed Faruq, Varun Suroliya, Manoj Kumar, Shilpa Sharma, Ralf Werner, Olaf Hiort und Vandana Jain. „Spectrum of Pathogenic Variants in SRD5A2 in Indian Children with 46,XY Disorders of Sex Development and Clinically Suspected Steroid 5α-Reductase 2 Deficiency“. Sexual Development 13, Nr. 5-6 (2019): 228–39. http://dx.doi.org/10.1159/000509812.
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The aim of this study was to assess the prevalence of pathogenic variants in the <i>SRD5A2</i> gene in children with 46,XY disorders of sex development (DSD) with normal to high serum testosterone levels and absence of Müllerian structures on imaging and to evaluate the genotype-phenotype correlation. Seventy-five patients with 46,XY DSD and probable clinical diagnosis of 5α-reductase 2 deficiency or androgen insensitivity syndrome were enrolled. Genetic analysis was done for pathogenic variants in <i>SRD5A2</i>, and the genotype-phenotype correlation was studied. As a result, 10 pathogenic or likely pathogenic biallelic variants in <i>SRD5A2, </i>either homozygous or compound heterozygous, were identified in 25 of 75 (33.3%) patients. The hCG stimulated testosterone: dihydrotestosterone (T:DHT) ratio was elevated in all patients with pathogenic variants in <i>SRD5A2</i> and in nearly 90% of those without pathogenic variants in <i>SRD5A2</i> in whom this was assessed. The missense pathogenic variant p.R246Q was a hotspot. One novel pathogenic variant p.Y178*, and a variant p.F194I, not previously reported in patients with 5α-reductase 2 deficiency, were identified. The missense variant p.F194I was predicted as deleterious and damaging by in silico analysis and as likely to reduce the enzyme activity by protein modeling. In conclusion, pathogenic variants in <i>SRD5A2 </i>can be detected in a wide spectrum of Indian patients with 46,XY DSD. Molecular genetic analysis should be considered as a first-line test as the T:DHT ratio lacks specificity and a hotspot variant is present in a vast majority.
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Othman, Houcemeddine, Jorge E. B. da Rocha und Scott Hazelhurst. „Single Nucleotide Polymorphism Induces Divergent Dynamic Patterns in CYP3A5: A Microsecond Scale Biomolecular Simulation of Variants Identified in Sub-Saharan African Populations“. International Journal of Molecular Sciences 22, Nr. 15 (21.07.2021): 7786. http://dx.doi.org/10.3390/ijms22157786.
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Pharmacogenomics aims to reveal variants associated with drug response phenotypes. Genes whose roles involve the absorption, distribution, metabolism, and excretion of drugs, are highly polymorphic between populations. High coverage whole genome sequencing showed that a large proportion of the variants for these genes are rare in African populations. This study investigated the impact of such variants on protein structure to assess their functional importance. We used genetic data of CYP3A5 from 458 individuals from sub-Saharan Africa to conduct a structural bioinformatics analysis. Five missense variants were modeled and microsecond scale molecular dynamics simulations were conducted for each, as well as for the CYP3A5 wildtype and the Y53C variant, which has a known deleterious impact on enzyme activity. The binding of ritonavir and artemether to CYP3A5 variant structures was also evaluated. Our results showed different conformational characteristics between all the variants. No significant structural changes were noticed. However, the genetic variability seemed to act on the plasticity of the protein. The impact on drug binding might be drug dependant. We concluded that rare variants hold relevance in determining the pharmacogenomics properties of populations. This could have a significant impact on precision medicine applications in sub-Saharan Africa.
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Kalús, Daniel, Daniela Koudelková, Veronika Mučková, Martin Sokol, Mária Kurčová und Patrik Šťastný. „Parametric study of the energy potential of a building’s envelope with integrated energy-active elements“. Acta Polytechnica 62, Nr. 6 (31.12.2022): 595–606. http://dx.doi.org/10.14311/ap.2022.62.0595.
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Building structures with integrated energy-active elements (BSIEAE) present a progressive alternative for building construction with multifunctional energy functions. The aim was to determine the energy potential of a building envelope with integrated energy-active elements in the function of direct-heating, semi-accumulation and accumulation of large-area radiant heating. The research methodology consists in an analysis of building structures with energy-active elements, creation of mathematical-physical models based on the simplified definition of heat and mass transfer in radiant large-area heating, and a parametric study of the energy potential of individual variants of technical solutions. The results indicate that the increase in heat loss due to the location of the tubes in the structure closer to the exterior is negligible for Variant II, semi-accumulation heating, and Variant III, accumulation heating, as compared to Variant I, direct heating, it is below 1 % of the total delivered heat flux. The direct heat flux to the heated room is 89.17 %, 73.36 %, and 58.46 % of the total heat flux for Variant I, Variant II and Variant III, respectively. For Variant II and Variant III, the heat storage accounts for 14.84 %, and 29.86 % of the total heat flux, respectively. Variants II and III appear to be promising in terms of heat/cool accumulation with an assumption of lower energy demand (at least 10 %) than for low inertia walls. We plan to extend these simplified parametric studies with dynamic computer simulations to optimise the design and composition of the panels with integrated energy-active elements.
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Perez, Jean Claude, Valère Lounnas und Montagnier Montagnier. „THE OMICRON VARIANT BREAKS THE EVOLUTIONARY LINEAGE OF SARS-COV2 VARIANTS“. International Journal of Research -GRANTHAALAYAH 9, Nr. 12 (30.12.2021): 108–32. http://dx.doi.org/10.29121/granthaalayah.v9.i12.2021.4418.
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We analyze here 7 very first strains of OMICRON the SARS-CoV2 new variant from South Africa, the USA (California and Minesota), Canada and Belgium. We applied, at the scale of the whole genome and the spike gene, the biomathematics method of Fibonacci meta-structure fractal analysis applied to the UA / CG proportions. We have evidenced the RUPTURE of OMICRON with respect to ALL the previous variants: D614G, ALPHA, BETA, GAMMA, DELTA. Remarkably, it is observed that the density of OMICRON mutations in the SPIKE PRION region is more than 8 times that of the rest of the Spike protein.
In particular, we suggest that the mRNA stabilizing secondary structure ("hairpin" conformation) in the spike of all variants is degraded in OMICRON, probably making its mRNA more fragile.
The loss of long-range fractal meta-structures in the OMICRON spike gene are in line with common knowledge on the mechanisms of epidemic ending, involving recombination of heavily mutated RNA fragments of the virus, with the possible inference of a distinct helper virus. This would indicate that the SARS-CoV2 is under very strong evolutionary pressure, possibly marking the end of the pandemic.
We are studying more particularly the prion-like region of the spike, the mutations rate of which is 8 times higher in OMICRON than that of the whole spike protein.
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Novak, Walter R. P., Basudeb Bhattacharyya, Daniel P. Grilley und Todd M. Weaver. „Proteolysis of truncated hemolysin A yields a stable dimerization interface“. Acta Crystallographica Section F Structural Biology Communications 73, Nr. 3 (21.02.2017): 138–45. http://dx.doi.org/10.1107/s2053230x17002102.
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Wild-type and variant forms of HpmA265 (truncated hemolysin A) fromProteus mirabilisreveal a right-handed, parallel β-helix capped and flanked by segments of antiparallel β-strands. The low-salt crystal structures form a dimeric structureviathe implementation of on-edge main-chain hydrogen bonds donated by residues 243–263 of adjacent monomers. Surprisingly, in the high-salt structures of two variants, Y134A and Q125A-Y134A, a new dimeric interface is formedviamain-chain hydrogen bonds donated by residues 203–215 of adjacent monomers, and a previously unobserved tetramer is formed. In addition, an eight-stranded antiparallel β-sheet is formed from the flap regions of crystallographically related monomers in the high-salt structures. This new interface is possible owing to additional proteolysis of these variants after Tyr240. The interface formed in the high-salt crystal forms of hemolysin A variants may mimic the on-edge β-strand positioning used in template-assisted hemolytic activity.
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Furuhara, Tadashi, Naoki Takayama und Goro Miyamoto. „Key Factors in Grain Refinement of Martensite and Bainite“. Materials Science Forum 638-642 (Januar 2010): 3044–49. http://dx.doi.org/10.4028/www.scientific.net/msf.638-642.3044.
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Grain refinement in lath martensite and bainite structures, which is important for strengthening and toughening, are discussed in various aspects. Strain accommodation plays important roles to determine final crystal sizes of bainitic ferrite (BF) and martensite. There is strong variant selection of BF by natures of the austenite grain boundary where it nucleates. For small undercooling, such variant selection leads to coarse bainite block and packet sizes. More BF variants are formed by increasing undercooling, which leads to nucleation of BF variants of less potency, and by increasing strength of materials, which results in more self-accommodation of transformation strain due to suppression of plastic accommodation. In lath martensite, there seems to be similar variant selection at austenite grain boundaries. However, packet/block sizes in lath martensite decreases with an increase in carbon content because of more extensive self-accommodation due to lower transformation temperatures than bainite.
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Tamayo-Ordóñez, Yahaira de J., Ninfa M. Rosas-García, Francisco A. Tamayo-Ordoñez, Benjamín A. Ayil-Gutiérrez, Juan M. Bello-López, Gerardo de J. Sosa-Santillán, Erika Acosta-Cruz et al. „Genomic Evolution Strategy in SARS-CoV-2 Lineage B: Coevolution of Cis Elements“. Current Issues in Molecular Biology 46, Nr. 6 (09.06.2024): 5744–76. http://dx.doi.org/10.3390/cimb46060344.
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In the SARS-CoV-2 lineage, RNA elements essential for its viral life cycle, including genome replication and gene expression, have been identified. Still, the precise structures and functions of these RNA regions in coronaviruses remain poorly understood. This lack of knowledge points out the need for further research to better understand these crucial aspects of viral biology and, in time, prepare for future outbreaks. In this research, the in silico analysis of the cis RNA structures that act in the alpha-, beta-, gamma-, and deltacoronavirus genera has provided a detailed view of the presence and adaptation of the structures of these elements in coronaviruses. The results emphasize the importance of these cis elements in viral biology and their variability between different viral variants. Some coronavirus variants in some groups, depending on the cis element (stem-loop1 and -2; pseudoknot stem-loop1 and -2, and s2m), exhibited functional adaptation. Additionally, the conformation flexibility of the s2m element in the SARS variants was determined, suggesting a coevolution of this element in this viral group. The variability in secondary structures suggests genomic adaptations that may be related to replication processes, genetic regulation, as well as the specific pathogenicity of each variant. The results suggest that RNA structures in coronaviruses can adapt and evolve toward different viral variants, which has important implications for viral adaptation, pathogenicity, and future therapeutic strategies.
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Mohsin, Duha Gheni, und Ali A. Abdul Kareem. „Genetic Variants of Insulin-Like Growth Factor 1 (IGF-1) Gene and Their Relationship with Productive Traits in Ross 308 Broilers“. IOP Conference Series: Earth and Environmental Science 1262, Nr. 7 (01.12.2023): 072066. http://dx.doi.org/10.1088/1755-1315/1262/7/072066.
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Abstract This study aimed to investigate the relationship between different genetic variants of the insulin-like growth factor 1 IGF-1 gene and some productive traits in Ross 308 broilers. A total of 150 one-day-old chicks were reared under good management conditions based on the rearing guide and a free-range feeding system. The birds were numbered, and their weights were recorded weekly to calculate weekly weight gain. Other weekly body measurements were also taken. After the rearing period, blood samples were collected from the birds via the wing vein, followed by slaughter and weighing of the carcass to determine the dressing percentage. The main and secondary cuts were weighed, and chest dimensions were measured. DNA was extracted, and three genetic structures were identified using sequencing technology, including GG, GT, and TT, with genetic structure proportions of 0.34, 0.58, and 0.08, respectively. The allele frequencies of G and T were 0.63 and 0.37, respectively. The results showed a significant superiority (P≤0.05) in weight and weekly weight gain for the TT genetic variant in the third, fourth, and fifth weeks compared to the other genetic variants (GT and GG). The TT variant also exhibited superiority in chest circumference in the third and fifth weeks and chest width in the third week. On the other hand, the TT and GG genetic variants showed superiority in chest width in the second and fourth weeks. The TT variant also demonstrated superiority in carcass weight and chest length compared to the other genetic variants. Moreover, the study revealed a significant increase (P≤0.05) in the dressing percentage, relative weight of the chest, wings, and back for the GT and GG genetic variants compared to the TT genetic variant. The GT variant also showed superiority in the relative weight of the thighs. However, there were no significant differences among the genetic variants in the relative weight of the neck and chest depth.
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Brennenstuhl, Heiko, Miroslava Didiasova, Birgit Assmann, Mariarita Bertoldi, Gianluca Molla, Sabine Jung-Klawitter, Oya Kuseyri Hübschmann, Julian Schröter, Thomas Opladen und Ritva Tikkanen. „Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of ALDH5A1“. International Journal of Molecular Sciences 21, Nr. 22 (13.11.2020): 8578. http://dx.doi.org/10.3390/ijms21228578.
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Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare, monogenic disorder affecting the degradation of the main inhibitory neurotransmitter γ-amino butyric acid (GABA). Pathogenic variants in the ALDH5A1 gene that cause an enzymatic dysfunction of succinic semialdehyde dehydrogenase (SSADH) lead to an accumulation of potentially toxic metabolites, including γ-hydroxybutyrate (GHB). Here, we present a patient with a severe phenotype of SSADHD caused by a novel genetic variant c.728T > C that leads to an exchange of leucine to proline at residue 243, located within the highly conserved nicotinamide adenine dinucleotide (NAD)+ binding domain of SSADH. Proline harbors a pyrrolidine within its side chain known for its conformational rigidity and disruption of protein secondary structures. We investigate the effect of this novel variant in vivo, in vitro, and in silico. We furthermore examine the mutational spectrum of all previously described disease-causing variants and computationally assess all biologically possible missense variants of ALDH5A1 to identify mutational hotspots.
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Hassan, Andrew Bassim Bassim, Rachael Wilkinson, Stuart Brown, Richard Wallbank, Mirvat Surakhy, Sofia Alves-Vasconcelos, Paul Metz et al. „AlphaMissense performance as a classifier of germline and somatic variants of unknown significance in high-grade sarcoma.“ Journal of Clinical Oncology 42, Nr. 16_suppl (01.06.2024): 11538. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.11538.
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11538 Background: Missense variants associated with high frequency, clinical context, splicing, penetrance and biochemical function are scored as pathogenic by ClinVar/ACMG (scores >99%/>90%). Pathogenic scores that range from this cut-point to 10% (benign) are referred to as variants of unknown significance (VUS). Alphafold2 is a deep neural network algorithm for protein structure trained on known molecular structures. It has informed AlphaMissense (AM) where the impact of every possible single missense variant in the human genome is assessed. The AM continuous pathogenicity score (roughly 0-0.35 benign, 0.36-0.55 ambiguous, 0.56-1.0 pathogenic) are claimed to have 90% accuracy based on ClinVar (based on 1,263 pathogenic and 1,263 benign variants). Methods: Here, we identified VUSs from the Oxford Sarcoma Precision Oncology real world cohort. This included the identification of somatic variants from FoundationOne Heme Sarcoma analysis of Formalin-Fixed Paraffin Embedded (FFPE) tumour samples. Germline variants were identified from whole exome sequencing (WES) (97 genes) from patient blood samples followed by analysis using GATK guidelines. All VUS identified were further analysed using AM. Results: AM reclassified the identified >1000 VUSs from 60 high grade sarcoma gene panels predominantly into benign or pathogenic, with only ~1% remaining as ambiguous. Variants reclassified as pathogenic were assessed for likelihood of pathogenicity based on scientific rationale. This involved evaluating current literature on the variant, determining evolutionary consensus of the residue, structural analysis to assess the potential function of the residue and enrichment of the variant within sarcoma patients compared to known frequencies across the population. Conclusions: In conclusion, the AM classifier dichotomises VUS to either benign or pathogenic, but this is not based on either structural or functional predictions directly. We conclude that it should not be currently used in the analysis of clinical samples seeking actionable variants but could instead stratify potential pathogenic variants for functional investigation.
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Razali, Nurul Nadirah, Raja Affendi Raja Ali, Khairul Najmi Muhammad Nawawi, Azyani Yahaya und Norfilza M. Mokhtar. „Targeted Sequencing of Cytokine-Induced PI3K-Related Genes in Ulcerative Colitis, Colorectal Cancer and Colitis-Associated Cancer“. International Journal of Molecular Sciences 23, Nr. 19 (29.09.2022): 11472. http://dx.doi.org/10.3390/ijms231911472.
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Chronic relapsing inflammatory bowel disease is strongly linked to an increased risk of colitis-associated cancer (CAC). One of the well-known inflammatory carcinogenesis pathways, phosphatidylinositol 3-kinase (PI3K), was identified to be a crucial mechanism in long-standing ulcerative colitis (UC). The goal of this study was to identify somatic variants in the cytokine-induced PI3K-related genes in UC, colorectal cancer (CRC) and CAC. Thirty biopsies (n = 8 long-standing UC, n = 11 CRC, n = 8 paired normal colorectal mucosa and n = 3 CAC) were subjected to targeted sequencing on 13 PI3K-related genes using Illumina sequencing and the SureSelectXT Target Enrichment System. The Genome Analysis Toolkit was used to analyze variants, while ANNOVAR was employed to detect annotations. There were 5116 intronic, 355 exonic, 172 untranslated region (UTR) and 59 noncoding intronic variations detected across all samples. Apart from a very small number of frameshifts, the distribution of missense and synonymous variants was almost equal. We discovered changed levels of IL23R, IL12Rß1, IL12Rß2, TYK2, JAK2 and OSMR in more than 50% of the samples. The IL23R variant in the UTR region, rs10889677, was identified to be a possible variant that might potentially connect CAC with UC and CRC. Additional secondary structure prediction using RNAfold revealed that mutant structures were more unstable than wildtype structures. Further functional research on the potential variants is, therefore, highly recommended since it may provide insight on the relationship between inflammation and cancer risk in the cytokine-induced PI3K pathway.
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Švajlenka, Jozef, Mária Kozlovská, Miroslav Badida, Marek Moravec, Tibor Dzuro und František Vranay. „Analysis of the Characteristics of External Walls of Wooden Prefab Cross Laminated Timber“. Energies 13, Nr. 22 (16.11.2020): 5974. http://dx.doi.org/10.3390/en13225974.
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A balanced combination of heat flows creates suitable conditions for thermal comfort—a factor contributing to the quality of the internal environment of buildings. The presented analysis of selected thermal-technical parameters is up-to-date and suitable for verifying the parameters of building constructions. The research also applied a methodology for examining the acoustic parameters of structural parts of buildings in laboratory conditions. In this research, selected variant solutions of perimeter walls based on prefab cross laminated timber were investigated in terms of acoustic and thermal-technical properties. The variants structures were investigated in laboratory but also in model conditions. The results of the analyses show significant differences between the theoretical or declared parameters and the values measured in laboratory conditions. The deviations of experimental measurements from the calculated or declared parameters were not as significant for variant B as they were for variant A. These findings show that for these analyzed sandwich structures based on wood, it is not always possible to reliably declare calculated values of thermal-technical and acoustic parameters. It is necessary to thoroughly examine such design variants, which would contribute to the knowledge in this field of research of construction systems based on wood.
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Jones, B., J. P. Tite und C. A. Janeway. „Different phenotypic variants of the mouse B cell tumor A20/2J are selected by antigen- and mitogen-triggered cytotoxicity of L3T4-positive, I-A-restricted T cell clones.“ Journal of Immunology 136, Nr. 1 (01.01.1986): 348–56. http://dx.doi.org/10.4049/jimmunol.136.1.348.
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Abstract The L3T4+, Lyt-2-, cloned BALB/c T cell lines 5.9.24 and 5.8.6 are cytotoxic for the BALB/c B cell tumor line A20/2J. The T cell cytotoxicity against A20/2J cells could be triggered either by the specific antigen ovalbumin (OVA), which is recognized by the T cell clones in association with I-Ad determinants, or by the T cell mitogens Con A and rabbit anti-mouse brain (RaMBr) antiserum. Repeated exposure of A20/2J cells to 5.9.24 and 5.8.6 T cell cytotoxicity selected variant cell lines that had developed resistance to cytotoxicity. The variant lines could be classified into four different variant phenotypes of which three were stably maintained in vitro. The type of variant obtained appeared to be related to the nature of the ligand used to trigger T cell cytotoxicity during selection. Cytotoxicity triggered by the antigen OVA generated type 1 variants that expressed abnormally low levels of I-Ad determinants at the cell surface. Type 1 variants were resistant to OVA-triggered 5.9.24 T cell cytotoxicity, but were fully susceptible to cytotoxicity triggered by Con A or RaMBr antiserum. RaMBr-triggered cytotoxicity generated two unique types of variant cell lines: type 3 variants that were deficient in cell surface Fc receptors and resistant to 5.9.24 cytotoxicity only when triggered by RaMBr antiserum, and type 4 variants that were resistant to cytotoxicity triggered by all three ligands. One type 4 variant, the IC-1 cell line, appeared to be resistant to soluble cytotoxic factors released by 5.9.24 T cells after activation by antigen. All of these variant lines retained sensitivity to cytotoxicity by classic Lyt-2+ cytotoxic T lymphocytes (CTL), a finding that indicates that L3T4a+ T cells and Lyt-2+ CTL use different molecules to attack their target cells. The variant phenotypes were inherited by clones derived from the original cell lines. Because the variants were generated without mutagenesis, they are thought to have been derived by the immunoselection of pre-existing variant cells that arose spontaneously in the parental A20/2J cell line. It is postulated that inheritable variation of A20/2J cells may represent changes that normally occur during B cell differentiation in response to T cell signals. The variant A20/2J cell lines described here provide material for the investigation of B cell surface structures that may regulate T-B cell interactions.
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Klochko, L. I. „Bearing Steel Structures for Installation of Railway Strain Gauge Scales“. Science and Transport Progress, Nr. 2(106) (18.06.2024): 80–89. http://dx.doi.org/10.15802/stp2024/306150.
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Purpose. The main purpose of the publication is to compare the main technical and economic indicators of the two proposed structural variants of the support system for railway strain gauge scales for four-axle wide gauge railcars. This is due to the need to reconstruct and modernize the fixed assets of an industrial enterprise, in particular, to overhaul and replace old railway scales with modern electronic strain gauge scales. Also, the purpose of the work is related to the need to expand the range of railway cars for which the possibility of weighing is provided, including transport units of the foreign car fleet. Methodology. To achieve this goal, we analyzed the modern types of railroad cars for freight transportation, determined the main components of strain gauge scales for weighing the main types of cars, and developed a special support system to support the scale platform. The support system is provided in two design variants - with one spatial support frame and two separate flat support frames. Using the domestic design and computing complex SCAD, we built finite element models for both proposed design options. Based on the analysis of their stress-strain state, rational cross-sections were selected for each structural element, and the total mass was determined. Findings. A comparative analysis of the two developed structural solutions for the support system for modern railway strain gauges has revealed that the variant with two separate bearing frames has a lower weight by about 40 % compared to the variant with one spatial bearing frame. However, the manufacturability of its production is somewhat lower, since it involves 10 structural elements compared to 7 for variant No. 1. Originality. The numerical analysis made it possible to theoretically substantiate a more rational and efficient design solution for the support system for modern railway strain gauge scales. Practical value. A constructive variant of the steel support system has been developed and proposed for practical implementation, which is the most effective in terms of its technical and economic indicators for the existing conditions of an existing industrial enterprise. The developed design option was also coordinated with the project of major reconstruction of the building for weighing railroad cars.
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Jin, Bowen, John A. Capra, Penelope Benchek, Nicholas Wheeler, Adam C. Naj, Kara L. Hamilton-Nelson, John J. Farrell et al. „An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease–related patterns“. Genome Research 32, Nr. 4 (24.02.2022): 778–90. http://dx.doi.org/10.1101/gr.276069.121.
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More than 90% of genetic variants are rare in most modern sequencing studies, such as the Alzheimer's Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data. Furthermore, 54% of the rare variants in ADSP WES are singletons. However, both single variant and unit-based tests are limited in their statistical power to detect an association between rare variants and phenotypes. To best use missense rare variants and investigate their biological effect, we examine their association with phenotypes in the context of protein structures. We developed a protein structure–based approach, protein optimized kernel evaluation of missense nucleotides (POKEMON), which evaluates rare missense variants based on their spatial distribution within a protein rather than their allele frequency. The hypothesis behind this test is that the three-dimensional spatial distribution of variants within a protein structure provides functional context to power an association test. POKEMON identified three candidate genes (TREM2, SORL1, and EXOC3L4) and another suggestive gene from the ADSP WES data. For TREM2 and SORL1, two known Alzheimer's disease (AD) genes, the signal from the spatial cluster is stable even if we exclude known AD risk variants, indicating the presence of additional low-frequency risk variants within these genes. EXOC3L4 is a novel AD risk gene that has a cluster of variants primarily shared by case subjects around the Sec6 domain. This cluster is also validated in an independent replication data set and a validation data set with a larger sample size.
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Frączek, Tadeusz, Michał Olejnik und Jarosław Jasiński. „Unconventional Short-Term Glow Discharge Nitriding of 316L Austenitic Steel“. Materials Science Forum 654-656 (Juni 2010): 366–69. http://dx.doi.org/10.4028/www.scientific.net/msf.654-656.366.
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The AISI 316L grade austenitic steel after glow discharge nitriding at a temperature of T = 598 K and for duration of = 10,8 ks, for different variants of specimen arrangement in the glow-discharge chamber was investigated. In the first variant specimens were placed on the cathode and in the second variant specimens were positioned also on the cathode, but shielded with a booster screen. In order to assess the effectiveness of nitriding process variants a profile analysis examination of obtained surface layers, surface hardness tests and surface layer hardness profile examination, analysis of surface layer structures and corrosion resistance tests were carried out. It was found that application of a booster screen effects in a nitrogen diffusion depth increment into the 316L austenitic steel, resulting in a surface layer thickness escalation.
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UEDA, Yoshihide, Makoto HIJIKATA, Shinji TAKAGI, Tsutomu CHIBA und Kunitada SHIMOTOHNO. „Transcriptional activities of p73 splicing variants are regulated by inter-variant association“. Biochemical Journal 356, Nr. 3 (08.06.2001): 859–66. http://dx.doi.org/10.1042/bj3560859.
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p73 has been identified as a gene that encodes a protein with significant identity with the tumour suppressor p53. The main structural difference between p73 and p53 is the additional C-terminal region of p73. Six isoforms of p73 with differing C-terminal structures, α, β, γ, δ, ∊ and ξ, have been reported. These variants differ in transcriptional activity on p53-responsive promoters. Here we report a possible mechanism of transcriptional activation by p73 splicing variants. C-terminal deletion mutants of p73α showed a significantly higher level of transcriptional activity than wild-type p73α, suggesting that the C-terminal structure of p73α functions to repress the transcriptional activity of p73α. The results of immunoprecipitation assays and two-hybrid assays in mammalian cells showed that the p73 variants interacted with each other, but not with p53. The transcriptional activity of p73β was reduced by co-expression with either p73α or p73∊, which bears an identical C-terminal structure to p73α. Co-expression of the C-terminal portion of p73α or p73∊ with p73β also resulted in reduced transcriptional activity. Moreover, we observed that the level of endogenous p21 protein induced by p73β was decreased by co-expression of full-length p73∊ or the C-terminal region of p73α or p73∊. These observations suggest that p73-mediated gene expression is regulated by the interactions of p73 splicing variants in the cell.
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Xiao, Binghe, Shaohua Zhang, Maierdanjiang Ainiwaer, Houyi Liu, Li Ning, Yingying Hong, Yang Sun und Yinghong Ji. „Deep learning–based assessment of missense variants in theCOG4gene presented with bilateral congenital cataract“. BMJ Open Ophthalmology 10, Nr. 1 (Januar 2025): e001906. https://doi.org/10.1136/bmjophth-2024-001906.
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ObjectiveWe compared the protein structure and pathogenicity of clinically relevant variants of theCOG4gene with AlphaFold2 (AF2), Alpha Missense (AM), and ThermoMPNN for the first time.Methods and analysisThe sequences of clinically relevant Cog4 missense variants (one novel identified p.Y714F and three pre-existing p.G512R, p.R729W and p.L769R from Uniprot Q9H9E3) were imported into AF2 for protein structural prediction, and the pathogenicity was estimated using AM and ThermoMPNN. Different pathogenicity metrics were aggregated with principal component analysis (PCA) and further analysed at three levels (amino acid position, substitution and post-translation) based on all possible Cog4 missense variants (n=14 915).ResultsLocalised protein structural impact including change of conformation and amino acid polarity, breakage of hydrogen bond and salt-bridge, and formation of alpha-helix were identified among clinically relevant Cog4 variants. The global structural comparison with multidimensional scaling demonstrated variants with similar protein structures (AF2) tended to exhibit similar clinical and biological phenotypes. The Cog4 p.Y714F variant exhibited greater protein structural similarity to mutated Cog4 found in Saul‒Wilson syndrome (p.G512R) and shared similar clinical phenotype (congenital cataract and psychomotor retardation). PCA of included pathogenic metrics demonstrated p.Y714F occurred at a critical position in Cog4 amino acid sequence with disrupted post-translational phosphorylation.ConclusionDeep learning algorithms, including AF2, AM and ThermoMPNN, can be useful for evaluating variant of uncertain significance (VUS) by structural and pathogenicity prediction. Despite classified as VUS (American College of Medical Genetics and Genomics criteria: PM1, PP4), the pathogenicity in this Cog4 variant cannot be ruled out and warrants further investigation.
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Malerba, Federica, Giulio Alberini, Ganna Balagura, Francesca Marchese, Elisabetta Amadori, Antonella Riva, Maria Stella Vari et al. „Genotype-phenotype correlations in patients with de novo KCNQ2 pathogenic variants“. Neurology Genetics 6, Nr. 6 (Dezember 2020): e528. http://dx.doi.org/10.1212/nxg.0000000000000528.
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ObjectiveEarly identification of de novo KCNQ2 variants in patients with epilepsy raises prognostic issues toward optimal management. We analyzed the clinical and genetic information from a cohort of patients with de novo KCNQ2 pathogenic variants to dissect genotype-phenotype correlations.MethodsPatients with de novo KCNQ2 pathogenic variants were identified from Italy, Denmark, and Belgium. Atomic resolution Kv7.2 structures were also generated using homology modeling to map the variants.ResultsWe included 34 patients with a mean age of 4.7 years. Median seizure onset was 2 days, mainly with focal seizures with autonomic signs. Twenty-two patients (65%) were seizure free at the mean age of 1.2 years. More than half of the patients (17/32) displayed severe/profound intellectual disability; however, 4 (13%) of them had a normal cognitive outcome.A total of 28 de novo pathogenic variants were identified, most missense (25/28), and clustered in conserved regions of the protein; 6 variants recurred, and 7 were novel. We did not identify a relationship between variant position and seizure offset or cognitive outcome in patients harboring missense variants. Besides, recurrent variants were associated with overlapping epilepsy features but also variable evolution regarding the intellectual outcome.ConclusionsWe highlight the complexity of variant interpretation to assess the impact of a class of de novo KCNQ2 mutations. Genetic modifiers could be implicated, but the study paradigms to successfully address the impact of each single mutation need to be developed.
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Popov, Vladimir O., Oleksandr V. Voitsehivskiy und Oleg V. Stinskiy. „COMPARISON OF THE EFFICIENCY OF RECONSTRUCTION METHODS OF STEEL-CONCRET SINGLE-SPAN BRIDGES“. Modern technology, materials and design in construction 34, Nr. 1 (30.07.2023): 19–26. http://dx.doi.org/10.31649/2311-1429-2023-1-19-26.
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The paper contains developed the method of strengthening steel-reinforced concrete single-span bridge structures that have undergone wear and tear due to long-term operation and require expansion. Have been described the structural solution and the principle of operation under load of the existing typical steel-reinforced concrete single-span bridges. As an example have been considered real emergency bridge structure in the village of Dashiv of the Haysyn district of the Vinnytsia region, in need of urgent reconstruction. Have been described in detail its main structural elements and technical condition. Have been shown possible rational ways of expanding and strengthening the structure in two variants. Variant 1 – reinforcement of existing steel and reinforced concrete structures with partial blocking of road traffic. Variant 2 – replacement of the span structure with a complete shutdown of the bridge for the duration of the construction and installation works. Have been developed basic constructive schemes for the reconstruction of the structure for the first and second variants. Have been described the technological sequence of strengthening the bridge structure according to both mentioned methods, have been analyzed the advantages and disadvantages and have been estimated the cost indicators of the reconstruction of each of the proposed variants. Have been proven that the strengthening method (variant 1) is more appropriate if it is necessary to partially operate the structure during construction and installation works. This method makes it possible to restore the design load-bearing capacity of the bridge structure with the provision of modern dimensional requirements and traffic safety requirements for less cost. The method of complete replacement of the span structure (variant 2), despite the higher cost, should be preferred in all other cases according to dynamics of constant growth of traffic flow in our country. With variant 2, it is possible to achieve not only the required dimensions, but also higher load-bearing characteristics of the bridge structure in a shorter period of time. The reliability and efficiency of each of the methods is confirmed by the corresponding strength calculations.
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Kowsari, Ali, Mahboobeh Rafigh, Mahsa Kazerani, Saba Fakharianzadeh und Abdolazim Sarli. „Identification of ARG1 Mutations in Patients with Arginase 1 Deficiency“. Clinical Medicine And Health Research Journal 2, Nr. 2 (18.04.2022): 99–102. http://dx.doi.org/10.18535/cmhrj.v2i2.40.
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Introduction: Argininemia is an autosomal recessive uncommon metabolic condition, caused by mutations in arginase enzyme. Variable clinical symptoms of argininemia might bring about a delayed diagnosis. In order to prove an argininemia condition, a genetic test result is needed. This study aims to describe two cases of argininemia homozygote mutations. Materials and Methods: Whole exome sequencing (WES) was utilized to detect disease causing variants. To prove adverse impacts of a novel variant and in silico analysis, PROVEAN web server is chosen. The effects of the novel mutation on the enzyme’s structure are shown in Chimera software using normal and mutated structures derived from SWISS model web server. Result: WES revealed two cases of autosomal recessive hyperargininemia. In one of the patients, a homozygous missense mutation of c.491G>A was detected, which is a novel ARG1 variant (p.Trp164Ter). Bioinformatics databases and the variant’s protein structure proved its deleterious effect on the enzyme’s function. The other patient was affected by a reported mutation of c.703G>A (p.G235R). Conclusion: The presence of various types of neurological and metabolic disorders with the same clinical findings with argininemia might lead to a lack of early diagnosis for beginning efficacious treatments. WES provides these patients with the opportunity to become diagnosed and receive therapies as early as possible.
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Cody, Vivian, Jim Pace, Hesham F. Nawar, Natalie King-Lyons, Shuang Liang, Terry D. Connell und George Hajishengallis. „Structure–activity correlations of variant forms of the B pentamer ofEscherichia colitype II heat-labile enterotoxin LT-IIb with Toll-like receptor 2 binding“. Acta Crystallographica Section D Biological Crystallography 68, Nr. 12 (09.11.2012): 1604–12. http://dx.doi.org/10.1107/s0907444912038917.
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The pentameric B subunit of the type II heat-labile enterotoxin ofEscherichia coli(LT-IIb-B5) is a potent signaling molecule capable of modulating innate immune responses. It has previously been shown that LT-IIb-B5, but not the LT-IIb-B5Ser74Asp variant [LT-IIb-B5(S74D)], activates Toll-like receptor (TLR2) signaling in macrophages. Consistent with this, the LT-IIb-B5(S74D) variant failed to bind TLR2, in contrast to LT-IIb-B5and the LT-IIb-B5Thr13Ile [LT-IIb-B5(T13I)] and LT-IIb-B5Ser74Ala [LT-IIb-B5(S74A)] variants, which displayed the highest binding activity to TLR2. Crystal structures of the Ser74Asp, Ser74Ala and Thr13Ile variants of LT-IIb-B5have been determined to 1.90, 1.40 and 1.90 Å resolution, respectively. The structural data for the Ser74Asp variant reveal that the carboxylate side chain points into the pore, thereby reducing the pore size compared with that of the wild-type or the Ser74Ala variant B pentamer. On the basis of these crystallographic data, the reduced TLR2-binding affinity of the LT-IIb-B5(S74D) variant may be the result of the pore of the pentamer being closed. On the other hand, the explanation for the enhanced TLR2-binding activity of the LT-IIb-B5(S74A) variant is more complex as its activity is greater than that of the wild-type B pentamer, which also has an open pore as the Ser74 side chain points away from the pore opening. Data for the LT-IIb-B5(T13I) variant show that four of the five variant side chains point to the outside surface of the pentamer and one residue points inside. These data are consistent with the lack of binding of the LT-IIb-B5(T13I) variant to GD1a ganglioside.
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Gruber, Lucinda, und L. James Maher. „Predicted Succinated Dehydrogenase Subunit Variant Pathogenicity: Why Are SDHB Variants “Bad”?“ Journal of the Endocrine Society 5, Supplement_1 (01.05.2021): A71—A72. http://dx.doi.org/10.1210/jendso/bvab048.144.
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Abstract Variants in the 4 genes encoding subunits A-D of succinate dehydrogenase (SDH) are associated with paraganglioma and pheochromocytoma. Intuitively, loss-of-function variants affecting any of the subunits should equally diminish SDH function leading to succinate accumulation and tumorigenesis after loss of heterozygosity. However, variants in SDHB are associated with a higher prevalence of metastatic disease and a more aggressive clinical course. Evaluation of the SDH protein structure shows the fraction of amino acids in contact with other subunits or essential prosthetic groups to be: 13% (SDHA), 40% (SDHB), 28% (SDHC), and 28% (SDHD). We therefore hypothesized that SDHB missense variants are more penetrant because a larger fraction alter sensitive interfaces with other SDH subunits or essential molecular features (e.g. the three SDHB iron-sulfur clusters). We also wondered if truncating variants are more common for SDHB than other subunits. To test these hypotheses, we combined three databases (Genome Aggregation Database, ClinVar-NCBI-NIH, and Leiden Open Variant Database) and our institution’s data to create a pool of all known SDH variants. We categorized variants as truncating or missense and evaluated missense variants in the context of the SDH protein structure, scoring each variant in relation to important structures/interfaces and the severity of the amino acid change. This provided an ad hoc impact score for each variant, where a higher score predicts a more deleterious effect. We compared these scores to those obtained using the “Sorting Intolerant from Tolerant” (SIFT) tool that predicts impacts of amino acid changes based on evolutionary sequence conservation. SIFT scores of 0 to 0.05 predict deleterious effects. Both mean impact and SIFT scores could be weighted for the prevalence of each variant in the population. Our database included 2333 total SDH variants: SDHA (838, 36%), SDHB (703, 30%), SDHC (381, 16%), and SDHD (412, 18%). The fractions of truncating variants were 38%, 50%, 51%, and 53% for A-D subunits, respectively. When weighted for prevalence, these fractions were 0.39%, 6.8%, 8.2%, and 0.2%. The number of truncating variants per coding region length and the distribution of locations were similar between subunits. Ad hoc impact scores for A-D subunits were 3.08, 14.9, 9.93, and 11.0, respectively and, when weighted for prevalence, were 0.28, 3.25, 6.32, and 1.15. Mean SIFT scores for subunits A-D were: 0.185, 0.162, 0.238, and 0.410 respectively, and, when weighted for prevalence, were 0.58, 0.70, 0.22, and 0.018. Our results do not support the hypothesis SDHB variants predict a worse clinical outcome because average SDHB variants are, by chance, more biochemically severe. This suggests that SDHB loss may uniquely impact SDH biochemical function.
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Janušaitis, Rytis. „ESTIMATION OF ALTERNATIVE WALL INSULATING SOLUTIONS USING THE METHOD OF TECHNOLOGICAL NETWORK MODEL “CUTTING OUT” JUNCTIONS/SIENŲ ŠILTINIMO ALTERNATYVIŲ SPRENDIMŲ ĮVERTINIMAS, TAIKANT TECHNOLOGINIO TINKLINIO MODELIO MAZGŲ “IŠPJOVIMO” METODĄ“. JOURNAL OF CIVIL ENGINEERING AND MANAGEMENT 4, Nr. 2 (30.06.1998): 161–70. http://dx.doi.org/10.3846/13921525.1998.10531397.
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The article investigates the problem of the dwelling house wall insulation of many-variant decisions estimation. At present multi-criteria evaluation methods are used. They provide the formal algorithm of the final effective selection of solution. However, during the optimisation of the decisions it is expedient to analyse the efficiency of intermediate decisions and those influencing the final findings. With that end in view the author suggests the multi- criteria problem of the evaluations of the variant decision using the method or technological network model of “cutting out” junctions. The main points of this method are: To cut out a comparable variant junction. Comparable variant junction is such a junction that contains at least two technological process variants. To determine comparable partial processes to the junction. To carry out a multi-criteria evaluation. To eliminate non-rational variants from further calculations. To pick out the most effective decision for the junction. From such decisions the complex process variants of wall insulation are made and multi-criteria evaluation is repeated. This method increases the abilities to raise the number of the partial alternative decisions for establishing the effectiveness ot the intermediate decisions, to receive and verify quickly final results of the decision evaluation and to decrease the amount of the calculations. “Cutting out” junction method can be used for estimating the decisions of building thermal renovation at the designing stage.
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Wang, Eric, und Arup K. Chakraborty. „Design of immunogens for eliciting antibody responses that may protect against SARS-CoV-2 variants“. PLOS Computational Biology 18, Nr. 9 (26.09.2022): e1010563. http://dx.doi.org/10.1371/journal.pcbi.1010563.
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The rise of SARS-CoV-2 variants and the history of outbreaks caused by zoonotic coronaviruses point to the need for next-generation vaccines that confer protection against variant strains. Here, we combined analyses of diverse sequences and structures of coronavirus spikes with data from deep mutational scanning to design SARS-CoV-2 variant antigens containing the most significant mutations that may emerge. We trained a neural network to predict RBD expression and ACE2 binding from sequence, which allowed us to determine that these antigens are stable and bind to ACE2. Thus, they represent viable variants. We then used a computational model of affinity maturation (AM) to study the antibody response to immunization with different combinations of the designed antigens. The results suggest that immunization with a cocktail of the antigens is likely to promote evolution of higher titers of antibodies that target SARS-CoV-2 variants than immunization or infection with the wildtype virus alone. Finally, our analysis of 12 coronaviruses from different genera identified the S2’ cleavage site and fusion peptide as potential pan-coronavirus vaccine targets.
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Yang, Tong, Yuan Yao, Xing Wang, Yuying Li, Yunlong Si, Xumin Li, Gabriela Jaramillo Ayala et al. „Galectin-13/placental protein 13: redox-active disulfides as switches for regulating structure, function and cellular distribution“. Glycobiology 30, Nr. 2 (07.10.2019): 120–29. http://dx.doi.org/10.1093/glycob/cwz081.
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Abstract Galectin-13 (Gal-13) plays numerous roles in regulating the relationship between maternal and fetal tissues. Low expression levels or mutations of the lectin can result in pre-eclampsia. The previous crystal structure and gel filtration data show that Gal-13 dimerizes via formation of two disulfide bonds formed by Cys136 and Cys138. In the present study, we mutated them to serine (C136S, C138S and C136S/C138S), crystalized the variants and solved their crystal structures. All variants crystallized as monomers. In the C136S structure, Cys138 formed a disulfide bond with Cys19, indicating that Cys19 is important for regulation of reversible disulfide bond formation in this lectin. Hemagglutination assays demonstrated that all variants are inactive at inducing erythrocyte agglutination, even though gel filtration profiles indicate that C136S and C138S could still form dimers, suggesting that these dimers do not exhibit the same activity as wild-type (WT) Gal-13. In HeLa cells, the three variants were found to be distributed the same as with WT Gal-13. However, a Gal-13 variant (delT221) truncated at T221 could not be transported into the nucleus, possibly explaining why women having this variant get pre-eclampsia. Considering the normally high concentration of glutathione in cells, WT Gal-13 should exist mostly as a monomer in cytoplasm, consistent with the monomeric variant C136S/C138S, which has a similar ability to interact with HOXA1 as WT Gal-13.