Search

Your search keyword '"Kini, U"' showing total 546 results
Start Over Author "Kini, U"
546 results on '"Kini, U"'

2. Dependence of pre-treatment structure on spheroidization and turning characteristics of AISI1040 steel

Author

Harisha S R, Sathyashankara Sharma, Ramakrishna Vikas Sadanand, Achutha Kini U, Raviraj Shetty, and Sathish Rao U

Subjects
Heat treatment, tool wear, surface roughness, machinability, DoE, Engineering (General). Civil engineering (General), TA1-2040
Abstract

AbstractDuring machinability, the combination of machining process parameters and the material properties of the component to be machined plays an important role. Material properties depend upon the type of phase form present and the grain size of the formed phases, which in turn depends upon the prior treatment given to alter the initial room temperature types and form. Accordingly, spheroidization treatment was carried out on medium carbon steel (AISI1040) by altering the initial room temperature structure through normalizing and hardening treatment. Machinability experiments were performed on CNC machine by varying machining process constraints. Tool wear and surface roughness of the machined component obtained by turning were analyzed and correlated. Using Minitab and full factorial design, the ANOVA study was carried out. With the help of regression analysis, residual and main effect plots combined optimization (tool wear and surface roughness) was targeted. ANOVA result shows excellent machinability for the as-bought-spheroidized condition where feed has a 67% contribution to tool wear (TW) whereas the depth of cut has a 71.91% contribution to surface roughness (SR). Also, the optimized regression values obtained for machining parameters are feed (0.39 mm/rev), depth of cut (0.6 mm), and spindle speed (780 rpm) with composite desirability of 0.8174. TW and SR experimental values for the optimized machining parameters are 0.039 mm and 2.89 μm, respectively, and the difference between the actual and optimized values is less than 5%.

Published
2023
Full Text
View/download PDF

3. Optimizing Capacitive Pressure Sensor Geometry: A Design of Experiments Approach with a Computer-Generated Model

Author

Kiran Keshyagol, Shivashankarayya Hiremath, Vishwanatha H. M., Achutha Kini U., Nithesh Naik, and Pavan Hiremath

Subjects
capacitive pressure sensor, sensitivity, dielectrics, optimization, design of experiment, PDMS, Chemical technology, TP1-1185
Abstract

This study presents a comprehensive investigation into the design and optimization of capacitive pressure sensors (CPSs) for their integration into capacitive touch buttons in electronic applications. Using the Finite Element Method (FEM), various geometries of dielectric layers were meticulously modeled and analyzed for their capacitive and sensitivity parameters. The flexible elastomer polydimethylsiloxane (PDMS) is used as a diaphragm, and polyvinylidene fluoride (PVDF) is a flexible material that acts as a dielectric medium. The Design of Experiment (DoE) techniques, aided by statistical analysis, were employed to identify the optimal geometric shapes of the CPS model. From the prediction using the DoE approach, it is observed that the cylindrical-shaped dielectric medium has better sensitivity. Using this optimal configuration, the CPS was further examined across a range of dielectric layer thicknesses to determine the capacitance, stored electrical energy, displacement, and stress levels at uniform pressures ranging from 0 to 200 kPa. Employing a 0.1 mm dielectric layer thickness yields heightened sensitivity and capacitance values, which is consistent with theoretical efforts. At a pressure of 200 kPa, the sensor achieves a maximum capacitance of 33.3 pF, with a total stored electric energy of 15.9 × 10−12 J and 0.468 pF/Pa of sensitivity for 0.1 dielectric thickness. These findings underscore the efficacy of the proposed CPS model for integration into capacitive touch buttons in electronic devices and e-skin applications, thereby offering promising advancements in sensor technology.

Published
2024
Full Text
View/download PDF

6. Detection and Control of Phishing Attack in Electronic Medical Record Application

Author

Aneesh Kini, U., Poornananda Bhat, M., Ganiga, Raghavendra, Pai, Radhika M., Manohara Pai, M. M., Shiva Prasad, H. C., Angrisani, Leopoldo, Series Editor, Arteaga, Marco, Series Editor, Panigrahi, Bijaya Ketan, Series Editor, Chakraborty, Samarjit, Series Editor, Chen, Jiming, Series Editor, Chen, Shanben, Series Editor, Chen, Tan Kay, Series Editor, Dillmann, Rüdiger, Series Editor, Duan, Haibin, Series Editor, Ferrari, Gianluigi, Series Editor, Ferre, Manuel, Series Editor, Hirche, Sandra, Series Editor, Jabbari, Faryar, Series Editor, Jia, Limin, Series Editor, Kacprzyk, Janusz, Series Editor, Khamis, Alaa, Series Editor, Kroeger, Torsten, Series Editor, Liang, Qilian, Series Editor, Martín, Ferran, Series Editor, Ming, Tan Cher, Series Editor, Minker, Wolfgang, Series Editor, Misra, Pradeep, Series Editor, Möller, Sebastian, Series Editor, Mukhopadhyay, Subhas, Series Editor, Ning, Cun-Zheng, Series Editor, Nishida, Toyoaki, Series Editor, Pascucci, Federica, Series Editor, Qin, Yong, Series Editor, Seng, Gan Woon, Series Editor, Speidel, Joachim, Series Editor, Veiga, Germano, Series Editor, Wu, Haitao, Series Editor, Zhang, Junjie James, Series Editor, Sengodan, Thangaprakash, editor, Murugappan, M., editor, and Misra, Sanjay, editor

Published
2020
Full Text
View/download PDF

8. Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype

Author

Sarli, C., van der Laan, L., Reilly, J., Trajkova, S., Carli, D., Brusco, A., Levy, M. A., Relator, R., Kerkhof, J., Mcconkey, H., Tedder, M. L., Skinner, C., Alders, M., Henneman, P., Hennekam, R. C. M., Ciaccio, C., D'Arrigo, S., Vitobello, A., Faivre, L., Weber, S., Vincent-Devulder, A., Perrin, L., Bourgois, A., Yamamoto, T., Metcalfe, K., Zollino, Marcella, Kini, U., Oliveira, D., Sousa, S. B., Williams, D., Cappuccio, G., Sadikovic, B., Brunetti-Pierri, N., Zollino M. (ORCID:0000-0003-4871-9519), Sarli, C., van der Laan, L., Reilly, J., Trajkova, S., Carli, D., Brusco, A., Levy, M. A., Relator, R., Kerkhof, J., Mcconkey, H., Tedder, M. L., Skinner, C., Alders, M., Henneman, P., Hennekam, R. C. M., Ciaccio, C., D'Arrigo, S., Vitobello, A., Faivre, L., Weber, S., Vincent-Devulder, A., Perrin, L., Bourgois, A., Yamamoto, T., Metcalfe, K., Zollino, Marcella, Kini, U., Oliveira, D., Sousa, S. B., Williams, D., Cappuccio, G., Sadikovic, B., Brunetti-Pierri, N., and Zollino M. (ORCID:0000-0003-4871-9519)

Abstract

Blepharophimosis with intellectual disability (BIS) is a recently recognized disorder distinct from Nicolaides-Baraister syndrome that presents with distinct facial features of blepharophimosis, developmental delay, and intellectual disability. BIS is caused by pathogenic variants in SMARCA2, that encodes the catalytic subunit of the superfamily II helicase group of the BRG1 and BRM-associated factors (BAF) forming the BAF complex, a chromatin remodeling complex involved in transcriptional regulation. Individuals bearing variants within the bipartite nuclear localization (BNL) signal domain of ADNP present with the neurodevelopmental disorder known as Helsmoortel-Van Der Aa Syndrome (HVDAS). Distinct DNA methylation profiles referred to as episignatures have been reported in HVDAS and BAF complex disorders. Due to molecular interactions between ADNP and BAF complex, and an overlapping craniofacial phenotype with narrowing of the palpebral fissures in a subset of patients with HVDAS and BIS, we hypothesized the possibility of a common phenotype-specific episignature. A distinct episignature was shared by 15 individuals with BIS-causing SMARCA2 pathogenic variants and 12 individuals with class II HVDAS caused by truncating pathogenic ADNP variants. This represents first evidence of a sensitive phenotype-specific episignature biomarker shared across distinct genetic conditions that also exhibit unique gene-specific episignatures.

Published
2024

9. Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data

Author

Fitzgerald, T.W., Gerety, S.S., Jones, W.D., van Kogelenberg, M., King, D.A., McRae, J., Morley, K.I., Parthiban, V., Al-Turki, S., Ambridge, K., Barrett, D.M., Bayzetinova, T., Clayton, S., Coomber, E.L., Gribble, S., Jones, P., Krishnappa, N., Mason, L.E., Middleton, A., Miller, R., Prigmore, E., Rajan, D., Sifrim, A., Tivey, A.R., Ahmed, M., Akawi, N., Andrews, R., Anjum, U., Archer, H., Armstrong, R., Balasubramanian, M., Banerjee, R., Barelle, D., Batstone, P., Baty, D., Bennett, C., Berg, J., Bernhard, B., Bevan, A.P., Blair, E., Blyth, M., Bohanna, D., Bourdon, L., Bourn, D., Brady, A., Bragin, E., Brewer, C., Brueton, L., Brunstrom, K., Bumpstead, S.J., Bunyan, D.J., Burn, J., Burton, J., Canham, N., Castle, B., Chandler, K., Clasper, S., Clayton-Smith, J., Cole, T., Collins, A., Collinson, M.N., Connell, F., Cooper, N., Cox, H., Cresswell, L., Cross, G., Crow, Y., D’Alessandro, P.M., Dabir, T., Davidson, R., Davies, S., Dean, J., Deshpande, C., Devlin, G., Dixit, A., Dominiczak, A., Donnelly, C., Donnelly, D., Douglas, A., Duncan, A., Eason, J., Edkins, S., Ellard, S., Ellis, P., Elmslie, F., Evans, K., Everest, S., Fendick, T., Fisher, R., Flinter, F., Foulds, N., Fryer, A., Fu, B., Gardiner, C., Gaunt, L., Ghali, N., Gibbons, R., Pereira, S.L. Gomes, Goodship, J., Goudie, D., Gray, E., Greene, P., Greenhalgh, L., Harrison, L., Hawkins, R., Hellens, S., Henderson, A., Hobson, E., Holden, S., Holder, S., Hollingsworth, G., Homfray, T., Humphreys, M., Hurst, J., Ingram, S., Irving, M., Jarvis, J., Jenkins, L., Johnson, D., Jones, D., Jones, E., Josifova, D., Joss, S., Kaemba, B., Kazembe, S., Kerr, B., Kini, U., Kinning, E., Kirby, G., Kirk, C., Kivuva, E., Kraus, A., Kumar, D., Lachlan, K., Lam, W., Lampe, A., Langman, C., Lees, M., Lim, D., Lowther, G., Lynch, S.A., Magee, A., Maher, E., Mansour, S., Marks, K., Martin, K., Maye, U., McCann, E., McConnell, V., McEntagart, M., McGowan, R., McKay, K., McKee, S., McMullan, D.J., McNerlan, S., Mehta, S., Metcalfe, K., Miles, E., Mohammed, S., Montgomery, T., Moore, D., Morgan, S., Morris, A., Morton, J., Mugalaasi, H., Murday, V., Nevitt, L., Newbury-Ecob, R., Norman, A., O’Shea, R., Ogilvie, C., Park, S., Parker, M.J., Patel, C., Paterson, J., Payne, S., Phipps, J., Pilz, D.T., Porteous, D., Pratt, N., Prescott, K., Price, S., Pridham, A., Proctor, A., Purnell, H., Ragge, N., Rankin, J., Raymond, L., Rice, D., Robert, L., Roberts, E., Roberts, G., Roberts, J., Roberts, P., Ross, A., Rosser, E., Saggar, A., Samant, S., Sandford, R., Sarkar, A., Schweiger, S., Scott, C., Scott, R., Selby, A., Seller, A., Sequeira, C., Shannon, N., Sharif, S., Shaw-Smith, C., Shearing, E., Shears, D., Simonic, I., Simpkin, D., Singzon, R., Skitt, Z., Smith, A., Smith, B., Smith, K., Smithson, S., Sneddon, L., Splitt, M., Squires, M., Stewart, F., Stewart, H., Suri, M., Sutton, V., Swaminathan, G.J., Sweeney, E., Tatton-Brown, K., Taylor, C., Taylor, R., Tein, M., Temple, I.K., Thomson, J., Tolmie, J., Torokwa, A., Treacy, B., Turner, C., Turnpenny, P., Tysoe, C., Vandersteen, A., Vasudevan, P., Vogt, J., Wakeling, E., Walker, D., Waters, J., Weber, A., Wellesley, D., Whiteford, M., Widaa, S., Wilcox, S., Williams, D., Williams, N., Woods, G., Wragg, C., Wright, M., Yang, F., Yau, M., Carter, N.P., Parker, M., Firth, H.V., FitzPatrick, D.R., Wright, C.F., Barrett, J.C., Hurles, M.E., Aitken, Stuart, Firth, Helen V., McRae, Jeremy, Halachev, Mihail, Kini, Usha, Parker, Michael J., Lees, Melissa M., Lachlan, Katherine, Sarkar, Ajoy, Joss, Shelagh, Splitt, Miranda, McKee, Shane, Németh, Andrea H., Scott, Richard H., Wright, Caroline F., Marsh, Joseph A., Hurles, Matthew E., and FitzPatrick, David R.

Published
2019
Full Text
View/download PDF

10. Micro-hardness variation of micro-phases during spheroidisation of AISI4340 steel

Author

Harisha S R, Sathyashankara Sharma, Achutha Kini U, Gurumurty B M, and Ananda Hegde

Subjects
aisi 4340 steel, spheroidisation, phase morphology, hardening, tensile strength, Engineering (General). Civil engineering (General), TA1-2040
Abstract

AISI4340 steel is the medium carbon low-alloy steel has got excellent prominence as a construction material. This steel is spheroidised on heating to the intercritical temperature range by different time intervals with the objective of increasing the number and fineness of the spheroids of cementite particles. A 9 hours, spheroidisation shows better spheroids of cementite particles. To study the effect of initial room temperature structure on spheroidisation primary heat treatments like normalising and hardening are carried out for as-bought steel. Tensile property (yield strength, ultimate tensile strength and percentage elongation), hardness (Rockwell C scale) and micro-structural features and micro-hardness of micro-phases (ferrite and cementite) are studied. A continuous reduction in the tensile strength, hardness and improvement in ductility, is observed with the increase in spheroidisation time is observed in all the spheroidisation paths. Also, increased spheroidisation time shows a lesser aspect ratio for spheroids. The micro-structure shows partial spheroidisation in all the conditions with more number of spheroids in normalised condition and finer size in hardened. Drastic reduction in strength and hardness values are observed in the hardened condition during spheroidisation.

Published
2021
Full Text
View/download PDF

11. Effect of intercritical processing temperature on mechanical properties, microstructure and microhardness of ferrite - bainite medium carbon dual phase steels

Author

Gurumurthy B M, Achutha Kini U, Sathyashankara Sharma, Pavan Hiremath, and Gowrishankar M C

Subjects
ferrite, bainite, martensite, dual phase, aisi1040, aisi4140, aisi4340, Engineering (General). Civil engineering (General), TA1-2040
Abstract

This research focusses on the dual phase (ferrite and bainite) treatment for medium carbon steels containing same carbon content (different alloying elements) and mechanical properties, as well as microhardness and microstructure. Dual phase treatment is carried out by heating normalized specimen to intercritical temperature range (750, 770 and 790 °C), followed by isothermal holding in the bainitic temperature (350 °C) and cooling to room temperature in still air. The effect of chemical composition (alloying elements) of steel on the dual phase morphology intern on the mechanical properties like, tensile strength, elongation, hardness and impact energy is also presented. Mechanical property results are in par with the microstructure and microhardnss of dual phase obtained. Lower intercritical temperature (750 °C) has resulted in lesser amount of bainite phase with poor mechanical properties in dual phase structure, whereas higher temperature (790 °C) increases bainite phase content with considerable improvement in mechanical properties. Microhardness data obtained supports the qualitative analysis of microstructure in all steels under consideration. It is found that intercritical temperature of dual phase treatment and material alloying elements are the major contributing factors on the dual phase microstructure and mechanical properties.

Published
2021
Full Text
View/download PDF

12. Investigation on tensile properties and analysis of wear property of glass fiber-epoxy-nanoclay ternary nanocomposite using response surface methodology

Author

Pavan Hiremath, Achutha Kini U, Manjunath Shettar, Sathyashankara Sharma, and Jayashree P K

Subjects
nanoclay, glass fiber, epoxy, tensile properties, wear property, response surface methodology, Engineering (General). Civil engineering (General), TA1-2040
Abstract

The current study’s objective is to investigate the impact of nanoclay on the tensile and wear properties of glass fiber-epoxy-nanoclay ternary nanocomposite. Three types of composites are produced by hand lay-up process and compression molding. Tensile and wear tests are executed according to ASTM standards. The findings disclosed that nanoclay enhanced the tensile properties of glass fiber-epoxy-nanoclay ternary nanocomposite. The causes for the failure under tensile load are revealed by SEM micrographs. Response surface methodology (RSM) is applied to analyse the wear loss of nanocomposite. The “Box–Behnken method” is employed for experimental design to establish the main and interaction effects among factors comprising nanoclay (NC), load, and sliding distance in three levels (0, 2, and 4 wt.% for nanoclay; 1, 3, and 5 kg for load; and 300, 600, and 900 rpm for sliding distance). The RSM offers a strong confidence model for each response. Also, RSM models are often used to estimate the optimum case with the minimum mass loss. The optimum results are estimated for the combination of 4 wt.% nanoclay, 1 kg load, and 300 rpm for sliding distance. Experimental test results revealed an agreement with the predicted values.

Published
2021
Full Text
View/download PDF

13. Investigation and analysis of aging behavior and tensile fracture study on precipitation hardened al7075-white cast iron particulate reinforced composites

Author

Gurumurthy B M, Jamaluddin Hindi, Achutha Kini U, and Sathya Shankara Sharma

Subjects
precipitation hardening, peak hardness, aging kinetics, tensile fracture, ultimate tensile strength, Engineering (General). Civil engineering (General), TA1-2040
Abstract

In this research work the machining waste white cast iron powder (WCI) is introduced in the age hardenable Al7075 alloy matrix with the objective of enhancing the tensile properties by well-known age hardening treatment. This material holds good in light duty dies where in the strength-related characteristics improvement is the order of the day. In view of this the effect of aging kinetics on the hardness pattern and tensile strength of stir cast Al7075-white cast iron (WCI) particulate reinforced composites in as cast and peak aging conditions is investigated. The composite is cast by two step liquid stir casting route. During precipitation hardening heat treatment, reinforcement weight percentage (internal variable) and aging temperature (external variable) are considered to be the major strengthening variables. To understand the nature of failure in tensile study, fracture surface analysis is carried out using SEM. The experimental values revealed that there is a substantial enhancement in the desired properties during the precipitation hardening treatment, if the strengthening variables are properly controlled. Hardness and tensile strength of the composite have increased with increase in weight percentage of reinforcement and reduction in aging temperature. Maximum hardness and tensile strength are observed when Al7075 alloy is reinforced with 6 weight% of WCI, aged at 100ᴼC. SEM images of tensile fracture surface exhibits abundant cup-like depressions or dimples as well as river patterns indicating mixed mode of failure. The equally aligned facets (dendrites) present in the peak-aged fracture surfaces is the evidence for the attainment of optimum (peak) aging condition. The aim of the present research work is to improve the hardness-related properties by the combined effect of precipitation of secondary phases (intermetallics) through aging treatment and dispersion strengthening by the introduction of hard reinforcement WCI.

Published
2021
Full Text
View/download PDF

16. Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Author

Schirwani, S., Albaba, S., Carere, D.A., Sacoto, M.J. Guillen, Zamora, F. Milan, Si, Y., Rabin, R., Pappas, J., Renaud, D.L., Hauser, N., Reid, E., Blanchet, P., Foulds, N., Dixit, A., Fisher, R., Armstrong, R., Isidor, B., Cogne, B., Vergano, S. Schrier, Demirdas, S., Dykzeul, N., Cohen, J.S., Grand, K., Morel, D., Slavotinek, A., Albassam, H.F., Naik, S., Dean, J., Ragge, N., Cinzia, C., Tedesco, M.G., Harrison, R.E., Bouman, A., Palen, E., Challman, T.D., Willemsen, M.H., Vogt, J., Cunniff, C., Bergstrom, K., Walia, J.S., Bruel, A.L., Kini, U., Alkuraya, F.S., Slegesky, V., Meeks, N., Girotto, P., Johnson, D., Newbury-Ecob, R., Ockeloen, C.W., Prontera, P., Lynch, S.A., Li, D., Graham, J.M., Balasubramanian, M., and Clinical Genetics

Subjects
Adult, Male, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Adolescent, Hypertelorism, Developmental Disabilities, speech impairment, Genetic Variation, ASXL3, BRPS, Young Adult, Phenotype, ASXL3-related syndrome, Bainbridge–Ropers syndrome, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, Mutation, Humans, Muscle Hypotonia, Female, Genetic Predisposition to Disease, Child, Transcription Factors
Abstract

Item does not contain fulltext The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

Published
2021
Full Text
View/download PDF

17. De novo missense variants in FBXO11 alter its protein expression and subcellular localization

Author

Gregor, A, Meerbrei, T, Gerstner, T, Toutain, A, Lynch, SA, Stals, K, Maxton, C, Lemke, JR, Bernat, JA, Bombei, HM, Foulds, N, Hunt, D, Kuechler, A, Beygo, J, Stobe, P, Bouman, A, Palomares-Bralo, M, Santos-Simarro, F, Garcia-Minaur, S, Pacio-Miguez, M, Popp, B, Vasileiou, G, Hebebrand, M, Reis, A, Schuhmann, S, Krumbiegel, M, Brown, NJ, Sparber, P, Melikyan, L, Bessonova, L, Cherevatova, T, Sharkov, A, Shcherbakova, N, Dabir, T, Kini, U, Schwaibold, EMC, Haack, TB, Bertoli, M, Hoffjan, S, Falb, R, Shinawi, M, Sticht, H, Zweier, C, Gregor, A, Meerbrei, T, Gerstner, T, Toutain, A, Lynch, SA, Stals, K, Maxton, C, Lemke, JR, Bernat, JA, Bombei, HM, Foulds, N, Hunt, D, Kuechler, A, Beygo, J, Stobe, P, Bouman, A, Palomares-Bralo, M, Santos-Simarro, F, Garcia-Minaur, S, Pacio-Miguez, M, Popp, B, Vasileiou, G, Hebebrand, M, Reis, A, Schuhmann, S, Krumbiegel, M, Brown, NJ, Sparber, P, Melikyan, L, Bessonova, L, Cherevatova, T, Sharkov, A, Shcherbakova, N, Dabir, T, Kini, U, Schwaibold, EMC, Haack, TB, Bertoli, M, Hoffjan, S, Falb, R, Shinawi, M, Sticht, H, and Zweier, C

Abstract

Recently, others and we identified de novo FBXO11 (F-Box only protein 11) variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data, our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs.

Published
2022

19. PURA-Related Developmental and Epileptic Encephalopathy

Author

Johannesen, K.M., Gardella, E., Gjerulfsen, C.E., Bayat, A., Rouhl, R.P.W., Reijnders, M., Whalen, S., Keren, B., Buratti, J., Courtin, T., Wierenga, K.J., Isidor, B., Piton, A., Faivre, L., Garde, A., Moutton, S., Tran-Mau-Them, F., Denomme-Pichon, A.S., Coubes, C., Larson, A., Esser, M.J., Appendino, J.P., Al-Hertani, W., Gamboni, B., Mampel, A., Mayorga, L., Orsini, A., Bonuccelli, A., Suppiej, A., Van-Gils, J., Vogt, J., Damioli, S., Giordano, L., Moortgat, S., Wirrell, E., Hicks, S., Kini, U., Noble, N., Stewart, H., Asakar, S., Cohen, J.S., Naidu, S.R., Collier, A., Brilstra, E.H., Li, M.H., Brew, C., Bigoni, S., Ognibene, D., Ballardini, E., Ruivenkamp, C., RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), and MUMC+: DA KG Polikliniek (9)

Subjects
ALPHA, DELINEATION, EPILEPSIES, DE-NOVO MUTATIONS, MORTALITY, FEATURES, PHENOTYPE, CLASSIFICATION, POSTNATAL BRAIN-DEVELOPMENT
Abstract

Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-alpha, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations.DiscussionThe PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

Published
2021

20. Hygrothermal Studies on GFRP Composites: A Review

Author

Shettar Manjunath, Chaudhary Aakarshit, Hussain Zaid, Kini U. Achutha, and Sharma Sathyashankara

Subjects
Hygrothermal Aging, GFRP, Accelerated Aging, Engineering (General). Civil engineering (General), TA1-2040
Abstract

The objective of this paper is to review the hygrothermal environment effects on Glass Fiber Reinforced Polymer (GFRP) composites. A brief summary of the hygrothermal phenomenon and its mechanisms of GFRP is followed by detailed review of hygrothermal effects on the GFRP. The review also includes the different hygrothermal aging tests viz., cold soaking, boiling soaking, thermal shocks and use of environmental chamber, procedures and significance. At the end, hygrothermal effects on the individual constituents of GFRP viz., fiber, matrix and the fiber-matrix interface, are discussed.

Published
2018
Full Text
View/download PDF

21. Study on Spheroidization and Related Heat Treatments of Medium Carbon Alloy Steels

Author

Harisha S. R., Sharma Sathyashankara, Kini U. Achutha, and Gowri Shankar M. C.

Subjects
Medium Carbon Steel, Heat Treatment, Spheroidizing, Microstructure, Annealing, Engineering (General). Civil engineering (General), TA1-2040
Abstract

The importance of medium carbon steels as engineering materials is reflected by the fact that out of the vast majority of engineering grade ferrous alloys available and used in the market today, a large proportion of them are from the family of medium carbon steels. Typically medium carbon steels have a carbon range of 0.25 to 0.65% by weight, and a manganese content ranging from 0.060 to 1.65% by weight. Medium carbon steels are more resistive to cutting, welding and forming as compared to low carbon steels. From the last two decades a number of research scholars reported the use of verity of heat treatments to tailor the properties of medium carbon steels. Spheroidizing is the novel industrial heat treatment employed to improve formability and machinability of medium/high carbon low alloy steels. This exclusive study covers procedure, the effects and possible outcomes of various heat treatments on medium carbon steels. In the present work, other related heat treatments like annealing and special treatments for property alterations which serve as pretreatments for spheroidizing are also reviewed. Medium carbon steels with property alterations by various heat treatment processes are finding increased responsiveness in transportation, aerospace, space, underwater along with other variegated fields. Improved tribological and mechanical properties consisting of impact resistance, stiffness, abrasion and strength are the main reasons for the increased attention of these steels in various industries. In the present scenario for the consolidation of important aspects of various heat treatments and effects on mechanical properties of medium carbons steel, a review of different research papers has been attempted. This review may be used as a guide to provide practical data for heat treatment industry, especially as a tool to enhance workability and tool life.

Published
2018
Full Text
View/download PDF

22. Root cause analysis of rough conical seat grinding problem in fuel pump cylinder head by Shainin methodology

Author

Kadam Sanket Shankar, Virupakshappa N. M., and Achutha Kini U.

Subjects
Engineering (General). Civil engineering (General), TA1-2040
Abstract

Problem solving plays a major role in quality engineering and it is popularly adopted by manufacturing industry. This study is aimed to determine root cause for rejection of cylinder head due to rough conical grinding problem by Shainin method. This has two major parts, first is diagnostic part which involves finding out the root cause and second is a remedial action part which consist of actual application of findings to rule out the problem. Wear in tool holder assembly is identified as root cause for rough grinding problem. Converging to root cause and validating the same achieved by successful implementation of Shainin tools.

Published
2018
Full Text
View/download PDF

25. Large-scale discovery of novel genetic causes of developmental disorders

Author

Fitzgerald, T. W., Gerety, S. S., Jones, W. D., van Kogelenberg, M., King, D. A., McRae, J., Morley, K. I., Parthiban, V., Al-Turki, S., Ambridge, K., Barrett, D. M., Bayzetinova, T., Clayton, S., Coomber, E. L., Gribble, S., Jones, P., Krishnappa, N., Mason, L. E., Middleton, A., Miller, R., Prigmore, E., Rajan, D., Sifrim, A., Tivey, A. R., Ahmed, M., Akawi, N., Andrews, R., Anjum, U., Archer, H., Armstrong, R., Balasubramanian, M., Banerjee, R., Baralle, D., Batstone, P., Baty, D., Bennett, C., Berg, J., Bernhard, B., Bevan, A. P., Blair, E., Blyth, M., Bohanna, D., Bourdon, L., Bourn, D., Brady, A., Bragin, E., Brewer, C., Brueton, L., Brunstrom, K., Bumpstead, S. J., Bunyan, D. J., Burn, J., Burton, J., Canham, N., Castle, B., Chandler, K., Clasper, S., Clayton-Smith, J., Cole, T., Collins, A., Collinson, M. N., Connell, F., Cooper, N., Cox, H., Cresswell, L., Cross, G., Crow, Y., DʼAlessandro, M., Dabir, T., Davidson, R., Davies, S., Dean, J., Deshpande, C., Devlin, G., Dixit, A., Dominiczak, A., Donnelly, C., Donnelly, D., Douglas, A., Duncan, A., Eason, J., Edkins, S., Ellard, S., Ellis, P., Elmslie, F., Evans, K., Everest, S., Fendick, T., Fisher, R., Flinter, F., Foulds, N., Fryer, A., Fu, B., Gardiner, C., Gaunt, L., Ghali, N., Gibbons, R., Pereira, Gomes S. L., Goodship, J., Goudie, D., Gray, E., Greene, P., Greenhalgh, L., Harrison, L., Hawkins, R., Hellens, S., Henderson, A., Hobson, E., Holden, S., Holder, S., Hollingsworth, G., Homfray, T., Humphreys, M., Hurst, J., Ingram, S., Irving, M., Jarvis, J., Jenkins, L., Johnson, D., Jones, D., Jones, E., Josifova, D., Joss, S., Kaemba, B., Kazembe, S., Kerr, B., Kini, U., Kinning, E., Kirby, G., Kirk, C., Kivuva, E., Kraus, A., Kumar, D., Lachlan, K., Lam, W., Lampe, A., Langman, C., Lees, M., Lim, D., Lowther, G., Lynch, S. A., Magee, A., Maher, E., Mansour, S., Marks, K., Martin, K., Maye, U., McCann, E., McConnell, V., McEntagart, M., McGowan, R., McKay, K., McKee, S., McMullan, D. J., McNerlan, S., Mehta, S., Metcalfe, K., Miles, E., Mohammed, S., Montgomery, T., Moore, D., Morgan, S., Morris, A., Morton, J., Mugalaasi, H., Murday, V., Nevitt, L., Newbury-Ecob, R., Norman, A., OʼShea, R., Ogilvie, C., Park, S., Parker, M. J., Patel, C., Paterson, J., Payne, S., Phipps, J., Pilz, D. T., Porteous, D., Pratt, N., Prescott, K., Price, S., Pridham, A., Procter, A., Purnell, H., Ragge, N., Rankin, J., Raymond, L., Rice, D., Robert, L., Roberts, E., Roberts, G., Roberts, J., Roberts, P., Ross, A., Rosser, E., Saggar, A., Samant, S., Sandford, R., Sarkar, A., Schweiger, S., Scott, C., Scott, R., Selby, A., Seller, A., Sequeira, C., Shannon, N., Sharif, S., Shaw-Smith, C., Shearing, E., Shears, D., Simonic, I., Simpkin, D., Singzon, R., Skitt, Z., Smith, A., Smith, B., Smith, K., Smithson, S., Sneddon, L., Splitt, M., Squires, M., Stewart, F., Stewart, H., Suri, M., Sutton, V., Swaminathan, G. J., Sweeney, E., Tatton-Brown, K., Taylor, C., Taylor, R., Tein, M., Temple, I. K., Thomson, J., Tolmie, J., Torokwa, A., Treacy, B., Turner, C., Turnpenny, P., Tysoe, C., Vandersteen, A., Vasudevan, P., Vogt, J., Wakeling, E., Walker, D., Waters, J., Weber, A., Wellesley, D., Whiteford, M., Widaa, S., Wilcox, S., Williams, D., Williams, N., Woods, G., Wragg, C., Wright, M., Yang, F., Yau, M., Carter, N. P., Parker, M., Firth, H. V., FitzPatrick, D. R., Wright, C. F., Barrett, J. C., and Hurles, M. E.

Published
2015
Full Text
View/download PDF

26. KAT6A Syndrome

Author

Kennedy, J., Goudie, D., Blair, E., Chandler, K., Joss, S., McKay, V., Green, A., Armstrong, R., Lees, M., Kamien, B., Hopper, B., Tan, T.Y., Yap, P., Stark, Z., Okamoto, N., Miyake, N., Matsumoto, N., Macnamara, E., Murphy, J.L., McCormick, E., Hakonarson, H., Falk, M.J., Li, D., Blackburn, P., Klee, E., Babovic-Vuksanovic, D., Schelley, S., Hudgins, L., Kant, S., Isidor, B., Cogne, B., Bradbury, K., Williams, M., Patel, C., Heussler, H., Duff-Farrier, C., Lakeman, P., Scurr, I., Kini, U., Elting, M., Reijnders, M., Schuurs-Hoeijmakers, J., Wafik, M., Blomhoff, A., Ruivenkamp, C.A.L., Nibbeling, E., Dingemans, A.J.M., Douine, E.D., Nelson, S.F., Hempel, M., Bierhals, T., Lessel, D., Johannsen, J., Arboleda, V.A., Newbury-Ecob, R., and DDD Study

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020
Full Text
View/download PDF

27. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Author

Hoed, J. den, Boer, E. de, Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L.J.M. van de, Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C.F., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P, Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S, Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A.K., Pfundt, R.P., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Snijders Blok, L., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-Dos-Santos, J.H., Schrier Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., Vissers, L.E.L.M., Hoed, J. den, Boer, E. de, Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L.J.M. van de, Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C.F., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P, Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S, Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A.K., Pfundt, R.P., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Snijders Blok, L., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-Dos-Santos, J.H., Schrier Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., and Vissers, L.E.L.M.

Abstract

Contains fulltext : 231687.pdf (Publisher’s version ) (Closed access), Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

Published
2021

28. Propanoyl(1Z)-N-(2,6-dimethylphenyl)-2-oxopropanehydrazonoate as inhibitor for corrosion of 6061 Al alloy15 % (v) SiC(p) composite in hydrochloric acid media

Author

Achutha Kini U, Prakasha Shetty, Divakara Shetty S, Ramadev Herle, and Arun Isloor

Subjects
Potentiostatic polarization, Aluminium alloy composite, Adsorption isotherm, Corrosion inhibition, Physisorption., Engineering (General). Civil engineering (General), TA1-2040
Abstract

ABSTRACT: The corrosion inhibition effect of Propanoyl(1Z)-N-(2,6-dimethylphenyl)-2-oxopropanehydrazonoate (PDOH) in the corrosion of 6061 Aluminium alloy-15%(v) SiC(p) composite in 0.5 and 1M hydrochloric acid medium at four different temperatures (30, 40, 50 and 60 ⁰C) was investigated using potentio-static polarization (Tafel extrapolation and Linear polarization) and weight loss methods. The results obtained reveal that PDOH is an efficient corrosion inhibitor with around 96% inhibition efficiency within the range of temperature studied. Leftward and downward shifts in Tafel plots were observed with the addition of the inhibitor, indicating that PDOH inhibits the corrosion process effectively, and that it is a cathodic inhibitor. Corrosion rate increases and inhibition efficiency decreases with increase in temperature. Results obtained by Tafel extrapolation, linear polarization, and weight loss methods are in agreement. The adsorption of the inhibitor onto the surface of the 6061 Al alloy 15 % (v) SiC(p) composite is found to obey Temkins' adsorption isotherm that verifies the assumption of mono-layer adsorption on a uniform homogeneous composite surface with an interaction in the adsorption layer. The inhibition is therefore governed by the physisorption mechanism. ABSTRAK: Kesan perencatan kakisan Propanoyl(1Z)-N-(2,6-dimethylphenyl)-2-oxopropanehydrazonoate (PDOH) ke atas kakisan komposit aloi Al 6061-15%(v) SiC(p) dalam media asid hidroklorik 0.5 dan 1M pada suhu-suhu yang berbeza (30, 40, 50 dan 60⁰C) telah dikaji menggunakan polarisasi statik-upaya (extrapolarisasi Tafel dan polarisasi Linear) dan kaedah kehilangan berat. Keputusan diperolehi menunjukkan PDOH adalah perencat yang efisien dengan 96 % keupayaan perencatan bagi julat suhu yag dikaji. Anjakan ke kiri dan ke bawah plot Tafel dapat dilihat dengan penambahan perencat, menunjukkan PDOH merencatkan proses kakisan dengan berkesan, dan ia adalah perencat katodik. Dengan peningkatan suhu, kadar kakisan meningkat dan keberkesanan perencatan menurun. Keputusan dari ekstrapolasi Tafel, polarisasi linear dan kehilangan berat.adalah saling bersetuju antara satu sama lain. Penjerapan perencat ke atas permukaan komposit aloi 6061 Al alloy 15 % (v) SiC(p) memenuhi penjerapan Temkins’ isoterma yang mengesahkan andaian penjerapan lapisan-mono ke atas permukaan komposit homogenus yang seragam melalui interaksi pada lapisan penjerapan. Perencatan dikawal oleh mekanisma fizijerapan.

Published
2012
Full Text
View/download PDF

29. STUDY OF LEFT VENTRICULAR FUNCTION BY SPECKLE TRACKING ECHOCARDIOGRAPHY AND CONVENTIONAL ECHOCARDIOGRAPHY IN PATIENTS WITH HYPERTHYROIDISM

Author

Thangasheela A, Pai Narasimha D, Monteiro Francis N. P, Namitha Kini U, and Kannan J

Subjects
03 medical and health sciences, medicine.medical_specialty, 0302 clinical medicine, Ventricular function, business.industry, Internal medicine, Cardiology, Medicine, 030209 endocrinology & metabolism, In patient, Speckle tracking echocardiography, 030204 cardiovascular system & hematology, business
Published
2018
Full Text
View/download PDF

30. The longer outcome of children born to mothers with epilepsy

Author

Adab, N., Kini, U., Vinten, J., Ayres, J., Baker, G., Clayton-Smith, J., Coyle, H., Fryer, A., Gorry, J., Gregg, J., Mawer, G., Nicolaides, P., Pickering, L., Tunnicliffe, L., and Chadwick, D.W.

Subjects
Prenatal drug exposure -- Complications and side effects, Prenatal drug exposure -- Case studies, Memory in children -- Complications and side effects, Memory in children -- Observations, Health, Psychology and mental health
Published
2004

40. Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder

Author

den Hoed, J., De Boer, E., Voisin, N., Guex, N., Blok, L. Snijders, Chrast, J., Manwaring, L., Willing, M., Waheeb, A., Osmond, M., McWalter, K., Vitobello, A., Demurger, F., Lavillaureix, A., Odent, S., Mazel, B., Faivre, L., Thiffault, I., Schwager, C., Amudhavalli, S. M., Rosenfeld, J. A., Radtke, K., Preiksaitiene, E., Ranza, E., Depienne, C., Kuechler, A., Mohammed, S., Abedi, Y. Hamzavi, Bonagura, V. R., Zuccarelli, B., Horist, B., Krishnamurthy, V., Kattentidt-Mouravieva, A. A., Granger, L., Petersen, A., Jones, K. L., Sinnema, M., Stegmann, A. P. A., Newbury-Ecob, R., Kini, U., Newbury, D. F., Gilissen, C., Brunner, H., Kleefstra, T., Reymond, A., Vissers, L. E. L. M., Fisher, S. E., Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Université de Lausanne (UNIL), Washington University in Saint Louis (WUSTL), GeneDx [Gaithersburg, MD, USA], Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Groupe Hospitalier Bretagne Sud (GHBS), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Ambry Genetics [Aliso Viejo, CA, USA], University of Kansas [Lawrence] (KU), Maastricht University [Maastricht], Radboud University [Nijmegen], Université de Lausanne = University of Lausanne (UNIL), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2020

41. Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

Author

Pagnamenta, A, Kaisaki, P, Bennett, F, Burkitt-Wright, E, Martin, H, Ferla, M, Taylor, J, Gompertz, L, Lahiri, N, Tatton-Brown, K, Newbury-Ecob, R, Henderson, A, Joss, S, Weber, A, Carmichael, J, Turnpenny, P, McKee, S, Forzano, F, Ashraf, T, Bradbury, K, Shears, D, Kini, U, De Burca, A, Study, The DDD, Blair, E, and Stewart, H

Subjects
Male, Heterozygote, Adolescent, Infant, Genes, Recessive, Original Articles, Pedigree, Cohort Studies, Gene Ontology, Phenotype, Child, Preschool, Mutation, RAS‐MAPK signalling, Humans, Noonan syndrome, Female, Original Article, Exome, LZTR1, Child, Alleles, developmental disorder, Transcription Factors, Genes, Dominant
Abstract

Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1‐associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly‐acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound‐heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss‐of‐function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS‐like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.‐38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1‐4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.

Published
2019
Full Text
View/download PDF

43. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor beta Signaling

Author

Johnson, B.V., Kumar, R., Oishi, S., Alexander, S., Kasherman, M., Vega, M.S., Ivancevic, A., Gardner, A., Domingo, D., Corbett, M., Parnell, E., Yoon, S., Oh, T., Lines, M., Lefroy, H., Kini, U., Allen, M., Gronborg, S., Mercier, S., Kury, S., Bezieau, S., Pasquier, L., Raynaud, M., Afenjar, A., Villemeur, T. Billette de, Keren, B., Desir, J., Maldergem, L. Van, Marangoni, M., Dikow, N., Koolen, D.A., VanHasselt, P.M., Weiss, M., Zwijnenburg, P., Sa, J., Reis, C.F., Lopez-Otin, C., Santiago-Fernandez, O., Fernandez-Jaen, A., Rauch, A., Steindl, K., Joset, P., Goldstein, A., Madan-Khetarpal, S., Infante, E., Zackai, E., McDougall, C., Narayanan, V., Ramsey, K., Mercimek-Andrews, S., Pena, L., Shashi, V., Schoch, K., Sullivan, J.A., Pinto, E.V.F., Pichurin, P.N., Ewing, S.A., Barnett, S.S., Klee, E.W., Perry, M.S., Koenig, M.K., Keegan, C.E., Schuette, J.L., Asher, S., Perilla-Young, Y., Smith, L.D., Rosenfeld, J.A., Bhoj, E., Kaplan, P., Li, D., Oegema, R., Binsbergen, E. van, Zwaag, B. van der, Smeland, M.F., Cutcutache, I., Page, M., Armstrong, M., Lin, A.E., Steeves, M.A., Hollander, N.D., Hoffer, M.J.V., Reijnders, M.R., Demirdas, S., Koboldt, D.C., Bartholomew, D., Mosher, T.M., Hickey, S.E., Shieh, C., Sanchez-Lara, P.A., Graham, J.M., Tezcan, K., Schaefer, G.B., Danylchuk, N.R., Asamoah, A., Jackson, K.E., Yachelevich, N., Au, M., Perez-Jurado, L.A., Kleefstra, T., Penzes, P., Gécz, J., Jolly, L.A., Johnson, B.V., Kumar, R., Oishi, S., Alexander, S., Kasherman, M., Vega, M.S., Ivancevic, A., Gardner, A., Domingo, D., Corbett, M., Parnell, E., Yoon, S., Oh, T., Lines, M., Lefroy, H., Kini, U., Allen, M., Gronborg, S., Mercier, S., Kury, S., Bezieau, S., Pasquier, L., Raynaud, M., Afenjar, A., Villemeur, T. Billette de, Keren, B., Desir, J., Maldergem, L. Van, Marangoni, M., Dikow, N., Koolen, D.A., VanHasselt, P.M., Weiss, M., Zwijnenburg, P., Sa, J., Reis, C.F., Lopez-Otin, C., Santiago-Fernandez, O., Fernandez-Jaen, A., Rauch, A., Steindl, K., Joset, P., Goldstein, A., Madan-Khetarpal, S., Infante, E., Zackai, E., McDougall, C., Narayanan, V., Ramsey, K., Mercimek-Andrews, S., Pena, L., Shashi, V., Schoch, K., Sullivan, J.A., Pinto, E.V.F., Pichurin, P.N., Ewing, S.A., Barnett, S.S., Klee, E.W., Perry, M.S., Koenig, M.K., Keegan, C.E., Schuette, J.L., Asher, S., Perilla-Young, Y., Smith, L.D., Rosenfeld, J.A., Bhoj, E., Kaplan, P., Li, D., Oegema, R., Binsbergen, E. van, Zwaag, B. van der, Smeland, M.F., Cutcutache, I., Page, M., Armstrong, M., Lin, A.E., Steeves, M.A., Hollander, N.D., Hoffer, M.J.V., Reijnders, M.R., Demirdas, S., Koboldt, D.C., Bartholomew, D., Mosher, T.M., Hickey, S.E., Shieh, C., Sanchez-Lara, P.A., Graham, J.M., Tezcan, K., Schaefer, G.B., Danylchuk, N.R., Asamoah, A., Jackson, K.E., Yachelevich, N., Au, M., Perez-Jurado, L.A., Kleefstra, T., Penzes, P., Gécz, J., and Jolly, L.A.

Abstract

Contains fulltext : 218305.pdf (Publisher’s version ) (Closed access), BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor beta signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory. CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hi

Published
2020

44. De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides–Baraitser syndrome

Author

Cappuccio, G., Sayou, C., Tanno, P. L., Tisserant, E., Bruel, A. -L., Kennani, S. E., Sa, J., Low, K. J., Dias, C., Havlovicova, M., Hancarova, M., Eichler, E. E., Devillard, F., Moutton, S., Van-Gils, J., Dubourg, C., Odent, S., Gerard, B., Piton, A., Yamamoto, T., Okamoto, N., Firth, H., Metcalfe, K., Moh, A., Chapman, K. A., Aref-Eshghi, E., Kerkhof, J., Torella, A., Nigro, V., Perrin, L., Piard, J., Le Guyader, G., Jouan, T., Thauvin-Robinet, C., Duffourd, Y., George-Abraham, J. K., Buchanan, C. A., Williams, D., Kini, U., Wilson, K., Brunetti-Pierri, N., Casari, G., Pinelli, M., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Capra, V., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Zollino, Marcella, Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Sousa, S. B., Hennekam, R. C. M., Sadikovic, B., Thevenon, J., Govin, J., Vitobello, A., Zollino M. (ORCID:0000-0003-4871-9519), Cappuccio, G., Sayou, C., Tanno, P. L., Tisserant, E., Bruel, A. -L., Kennani, S. E., Sa, J., Low, K. J., Dias, C., Havlovicova, M., Hancarova, M., Eichler, E. E., Devillard, F., Moutton, S., Van-Gils, J., Dubourg, C., Odent, S., Gerard, B., Piton, A., Yamamoto, T., Okamoto, N., Firth, H., Metcalfe, K., Moh, A., Chapman, K. A., Aref-Eshghi, E., Kerkhof, J., Torella, A., Nigro, V., Perrin, L., Piard, J., Le Guyader, G., Jouan, T., Thauvin-Robinet, C., Duffourd, Y., George-Abraham, J. K., Buchanan, C. A., Williams, D., Kini, U., Wilson, K., Brunetti-Pierri, N., Casari, G., Pinelli, M., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Capra, V., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Zollino, Marcella, Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Sousa, S. B., Hennekam, R. C. M., Sadikovic, B., Thevenon, J., Govin, J., Vitobello, A., and Zollino M. (ORCID:0000-0003-4871-9519)

Abstract

Purpose: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides–Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown. Methods: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes. Results: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification. Conclusion: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

Published
2020

48. Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders

Author

Evers, JMG, Laskowski, RA, Bertolli, M, Clayton-Smith, J, Deshpande, C, Eason, J, Elmslie, F, Flinter, F, Gardiner, C, Hurst, JA, Kingston, H, Kini, U, Lampe, AK, Lim, D, Male, A, Naik, S, Parker, MJ, Price, S, Robert, L, Sarkar, A, Straub, V, Woods, G, Thornton, JM, DDD Study, and Wright, CF

Subjects
0301 basic medicine, Male, DYRK1A, Protein Conformation, Developmental Disabilities, Mutation, Missense, Haploinsufficiency, Biology, Protein Serine-Threonine Kinases, medicine.disease_cause, DYRK1A Gene, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, Intellectual Disability, Genetics, medicine, Missense mutation, Humans, Autistic Disorder, Molecular Biology, Gene, Genetics (clinical), Mutation, General Medicine, Articles, Protein-Tyrosine Kinases, Phenotype, Pedigree, 030104 developmental biology, Protein kinase domain, Female, 030217 neurology & neurosurgery
Abstract

Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is currently unclear. Here we present 19 de novo mutations in this gene, including five missense mutations, identified by the Deciphering Developmental Disorder study. Protein structural analysis reveals that the missense mutations are either close to the ATP or peptide binding-sites within the kinase domain, or are important for protein stability, suggesting they lead to a loss of the protein’s function mechanism. Furthermore, there is some correlation between the magnitude of the change and the severity of the resultant phenotype. A comparison of the distribution of the pathogenic mutations along the length of DYRK1A with that of natural variants, as found in the ExAC database, confirms that mutations in the N-terminal end of the kinase domain are more disruptive of protein function. In particular, pathogenic mutations occur in significantly closer proximity to the ATP and the substrate peptide than the natural variants. Overall, we suggest that de novo dominant mutations in DYRK1A account for nearly 0.5% of severe developmental disorders due to substantially reduced kinase function.

Published
2017
Full Text
View/download PDF

49. Activation of an exonic splice‐donor site in exon 30 of CDK5RAP2 in a patient with severe microcephaly and pigmentary abnormalities

Author

Pagnamenta, A, Howard, M, Knight, S, Keays, D, Quaghebeur, G, Taylor, J, and Kini, U

Subjects
CDK5RAP2, exonic splice‐donor, Case Report, pigmentation abnormalities, Case Reports, microcephaly, exome
Abstract

Key Clinical Message This report constitutes the first report of a cryptic exonic splice‐donor site in CDK5RAP2, highlights the importance of evaluating novel splice mutations, and suggests that the phenotypic range associated with CDK5RAP2 mutations may include skin pigmentary abnormalities.

Published
2016

50. A homozygous variant disrupting the PIGH start-codon is associated with developmental delay, epilepsy, and microcephaly

Author

Pagnamenta, A, Murakami, Y, Anzilotti, C, Titheradge, H, Oates, A, Morton, J, Study, DDD, Kinoshita, T, Kini, U, Taylor, J, Pagnamenta, Alistair T [0000-0001-7334-0602], Murakami, Yoshiko [0000-0002-4870-5734], and Apollo - University of Cambridge Repository

Subjects
Male, Epilepsy, Adolescent, Glycosylphosphatidylinositols, Developmental Disabilities, phosphatidylinositol N-acetylglucosaminyltransferase, Codon, Initiator, Membrane Proteins, Pedigree, developmental delay, PIGH, Child, Preschool, Cricetinae, Mutation, Microcephaly, Animals, Humans, Exome, Female, Child, GPI-anchor biogenesis
Abstract

Defective glycosylphosphatidylinositol (GPI)‐anchor biogenesis can cause a spectrum of predominantly neurological problems. For eight genes critical to this biological process, disease associations are not yet reported. Scanning exomes from 7,833 parent–child trios and 1,792 singletons from the DDD study for biallelic variants in this gene‐set uncovered a rare PIGH variant in a boy with epilepsy, microcephaly, and behavioral difficulties. Although only 2/2 reads harbored this c.1A > T transversion, the presence of ∼25 Mb autozygosity at this locus implied homozygosity, which was confirmed using Sanger sequencing. A similarly‐affected sister was also homozygous. FACS analysis of PIGH‐deficient CHO cells indicated that cDNAs with c.1A > T could not efficiently restore expression of GPI‐APs. Truncation of PIGH protein was consistent with the utilization of an in‐frame start‐site at codon 63. In summary, we describe siblings harboring a homozygous c.1A > T variant resulting in defective GPI‐anchor biogenesis and highlight the importance of exploring low‐coverage variants within autozygous regions.

Published
2019
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results