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Publisher: Oxford University Press   (Total: 396 journals)

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Showing 1 - 200 of 396 Journals sorted alphabetically
ACS Symposium Series     Full-text available via subscription  
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.881, h-index: 38)
Adaptation     Hybrid Journal   (Followers: 8, SJR: 0.111, h-index: 4)
Advances in Nutrition     Hybrid Journal   (Followers: 43, SJR: 2.075, h-index: 36)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.538, h-index: 35)
African Affairs     Hybrid Journal   (Followers: 64, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 87, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 18, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 6)
American Historical Review     Hybrid Journal   (Followers: 154, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 40, SJR: 1.441, h-index: 77)
American J. of Clinical Nutrition     Hybrid Journal   (Followers: 144, SJR: 3.771, h-index: 262)
American J. of Epidemiology     Hybrid Journal   (Followers: 169, SJR: 3.047, h-index: 201)
American J. of Hypertension     Hybrid Journal   (Followers: 25, SJR: 1.397, h-index: 111)
American J. of Jurisprudence     Hybrid Journal   (Followers: 18)
American J. of Legal History     Full-text available via subscription   (Followers: 8, SJR: 0.151, h-index: 7)
American Law and Economics Review     Hybrid Journal   (Followers: 27, SJR: 0.824, h-index: 23)
American Literary History     Hybrid Journal   (Followers: 15, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 21)
Animal Frontiers     Hybrid Journal  
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 14, SJR: 2.112, h-index: 98)
Annals of Botany     Hybrid Journal   (Followers: 35, SJR: 1.912, h-index: 124)
Annals of Oncology     Hybrid Journal   (Followers: 47, SJR: 4.362, h-index: 173)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 9, SJR: 0.642, h-index: 53)
Annals of Work Exposures and Health     Hybrid Journal   (Followers: 30, SJR: 0.837, h-index: 57)
AoB Plants     Open Access   (Followers: 4, SJR: 0.78, h-index: 10)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 16, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 56, SJR: 1.749, h-index: 63)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 0.779, h-index: 11)
Arbitration Intl.     Full-text available via subscription   (Followers: 20)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 14)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 30, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 3, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 42, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 51, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 294, SJR: 4.643, h-index: 271)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 10, SJR: 1.646, h-index: 149)
Biometrika     Hybrid Journal   (Followers: 20, SJR: 2.801, h-index: 90)
BioScience     Hybrid Journal   (Followers: 30, SJR: 2.374, h-index: 154)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.213, h-index: 9)
Biostatistics     Hybrid Journal   (Followers: 17, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 160, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 64, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 68, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 46, SJR: 4.086, h-index: 73)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 3, SJR: 1.771, h-index: 50)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 34, SJR: 1.267, h-index: 38)
British J. of Aesthetics     Hybrid Journal   (Followers: 26, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 585, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 87, SJR: 0.771, h-index: 53)
British Medical Bulletin     Hybrid Journal   (Followers: 7, SJR: 1.391, h-index: 84)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 31)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 4, SJR: 1.474, h-index: 31)
Cambridge J. of Economics     Hybrid Journal   (Followers: 61, SJR: 0.957, h-index: 59)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 10, SJR: 1.067, h-index: 22)
Cambridge Quarterly     Hybrid Journal   (Followers: 9, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal   (Followers: 2)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.439, h-index: 167)
Cardiovascular Research     Hybrid Journal   (Followers: 13, SJR: 2.897, h-index: 175)
Cerebral Cortex     Hybrid Journal   (Followers: 45, SJR: 4.827, h-index: 192)
CESifo Economic Studies     Hybrid Journal   (Followers: 17, SJR: 0.501, h-index: 19)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.436, h-index: 76)
Children and Schools     Hybrid Journal   (Followers: 5, SJR: 0.211, h-index: 18)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 4)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 22, SJR: 0.737, h-index: 11)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 9, SJR: 1.238, h-index: 15)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 10, SJR: 0.191, h-index: 8)
Classical Receptions J.     Hybrid Journal   (Followers: 25, SJR: 0.1, h-index: 3)
Clean Energy     Open Access   (Followers: 1)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 62, SJR: 4.742, h-index: 261)
Clinical Kidney J.     Open Access   (Followers: 3, SJR: 0.338, h-index: 19)
Communication Theory     Hybrid Journal   (Followers: 21, SJR: 2.62, h-index: 53)
Communication, Culture & Critique     Hybrid Journal   (Followers: 25)
Community Development J.     Hybrid Journal   (Followers: 27, SJR: 0.47, h-index: 28)
Computer J.     Hybrid Journal   (Followers: 9, SJR: 0.371, h-index: 47)
Conservation Physiology     Open Access   (Followers: 2)
Contemporary Women's Writing     Hybrid Journal   (Followers: 9, SJR: 0.111, h-index: 3)
Contributions to Political Economy     Hybrid Journal   (Followers: 5, SJR: 0.313, h-index: 10)
Critical Values     Full-text available via subscription  
Current Developments in Nutrition     Open Access  
Current Legal Problems     Hybrid Journal   (Followers: 27)
Current Zoology     Full-text available via subscription   (Followers: 2, SJR: 0.999, h-index: 20)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 8, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 13)
Diplomatic History     Hybrid Journal   (Followers: 20, SJR: 0.296, h-index: 22)
DNA Research     Open Access   (Followers: 5, SJR: 2.42, h-index: 77)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 3)
Early Music     Hybrid Journal   (Followers: 15, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 39, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 24, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 51, SJR: 0.311, h-index: 10)
English: J. of the English Association     Hybrid Journal   (Followers: 14, SJR: 0.144, h-index: 3)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.791, h-index: 66)
Environmental Epigenetics     Open Access   (Followers: 3)
Environmental History     Hybrid Journal   (Followers: 26, SJR: 0.197, h-index: 25)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.201, h-index: 71)
Epidemiologic Reviews     Hybrid Journal   (Followers: 9, SJR: 3.917, h-index: 81)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 16, SJR: 0.1, h-index: 6)
European Heart J.     Hybrid Journal   (Followers: 54, SJR: 6.997, h-index: 227)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 8, SJR: 2.044, h-index: 58)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 1)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. : Case Reports     Open Access  
European Heart J. Supplements     Hybrid Journal   (Followers: 7, SJR: 0.152, h-index: 31)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 9, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 176, SJR: 0.722, h-index: 38)
European J. of Orthodontics     Hybrid Journal   (Followers: 4, SJR: 1.09, h-index: 60)
European J. of Public Health     Hybrid Journal   (Followers: 20, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 10, SJR: 1.549, h-index: 42)
European Review of Economic History     Hybrid Journal   (Followers: 28, SJR: 0.628, h-index: 24)
European Sociological Review     Hybrid Journal   (Followers: 40, SJR: 2.061, h-index: 53)
Evolution, Medicine, and Public Health     Open Access   (Followers: 10)
Family Practice     Hybrid Journal   (Followers: 14, SJR: 1.048, h-index: 77)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 10, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 22, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 27, SJR: 7.587, h-index: 150)
Fems Yeast Research     Hybrid Journal   (Followers: 14, SJR: 1.213, h-index: 66)
Food Quality and Safety     Open Access  
Foreign Policy Analysis     Hybrid Journal   (Followers: 23, SJR: 0.859, h-index: 10)
Forest Science     Hybrid Journal   (Followers: 7, SJR: 0.872, h-index: 59)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 0.903, h-index: 44)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.108, h-index: 6)
French History     Hybrid Journal   (Followers: 32, SJR: 0.123, h-index: 10)
French Studies     Hybrid Journal   (Followers: 20, SJR: 0.119, h-index: 7)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.102, h-index: 3)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 12, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 35, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 22, SJR: 0.437, h-index: 13)
GigaScience     Open Access   (Followers: 3)
Global Summitry     Hybrid Journal   (Followers: 1)
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.692, h-index: 101)
Health and Social Work     Hybrid Journal   (Followers: 55, SJR: 0.505, h-index: 40)
Health Education Research     Hybrid Journal   (Followers: 13, SJR: 0.814, h-index: 80)
Health Policy and Planning     Hybrid Journal   (Followers: 24, SJR: 1.628, h-index: 66)
Health Promotion Intl.     Hybrid Journal   (Followers: 21, SJR: 0.664, h-index: 60)
History Workshop J.     Hybrid Journal   (Followers: 29, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 26, SJR: 0.115, h-index: 13)
Human Communication Research     Hybrid Journal   (Followers: 13, SJR: 2.199, h-index: 61)
Human Molecular Genetics     Hybrid Journal   (Followers: 8, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 72, SJR: 2.271, h-index: 179)
Human Reproduction Open     Open Access  
Human Reproduction Update     Hybrid Journal   (Followers: 19, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 60, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 50, SJR: 1.233, h-index: 88)
ICSID Review     Hybrid Journal   (Followers: 11)
ILAR J.     Hybrid Journal   (Followers: 2, SJR: 1.099, h-index: 51)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.329, h-index: 26)
IMA J. of Management Mathematics     Hybrid Journal   (SJR: 0.351, h-index: 20)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.661, h-index: 28)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 2.032, h-index: 44)
Industrial and Corporate Change     Hybrid Journal   (Followers: 10, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 35, SJR: 0.184, h-index: 15)
Inflammatory Bowel Diseases     Hybrid Journal   (Followers: 42, SJR: 1.994, h-index: 107)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 7, SJR: 1.911, h-index: 90)
Interacting with Computers     Hybrid Journal   (Followers: 11, SJR: 0.529, h-index: 59)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 6, SJR: 0.743, h-index: 35)
Intl. Affairs     Hybrid Journal   (Followers: 57, SJR: 1.264, h-index: 53)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 31)
Intl. Health     Hybrid Journal   (Followers: 5, SJR: 0.835, h-index: 15)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 1.613, h-index: 111)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 34, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 63, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 206, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 5, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 31, SJR: 0.307, h-index: 15)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 10, SJR: 0.404, h-index: 18)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.457, h-index: 12)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.69, h-index: 79)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 9, SJR: 0.906, h-index: 33)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 35, SJR: 0.231, h-index: 21)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 12, SJR: 0.833, h-index: 12)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.052, h-index: 42)
Intl. Political Sociology     Hybrid Journal   (Followers: 36, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 22, SJR: 0.539, h-index: 17)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.998, h-index: 28)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 44, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 21, SJR: 0.783, h-index: 38)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 1, SJR: 0.155, h-index: 4)
ITNOW     Hybrid Journal   (Followers: 1, SJR: 0.102, h-index: 4)
J. of African Economies     Hybrid Journal   (Followers: 14, SJR: 0.647, h-index: 30)
J. of American History     Hybrid Journal   (Followers: 45, SJR: 0.286, h-index: 34)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 14, SJR: 1.038, h-index: 60)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 15, SJR: 2.157, h-index: 149)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 4, SJR: 0.563, h-index: 43)
J. of Biochemistry     Hybrid Journal   (Followers: 42, SJR: 1.341, h-index: 96)
J. of Burn Care & Research     Hybrid Journal   (Followers: 9, SJR: 0.713, h-index: 57)
J. of Chromatographic Science     Hybrid Journal   (Followers: 18, SJR: 0.448, h-index: 42)
J. of Church and State     Hybrid Journal   (Followers: 11, SJR: 0.167, h-index: 11)
J. of Communication     Hybrid Journal   (Followers: 50, SJR: 3.327, h-index: 82)
J. of Competition Law and Economics     Hybrid Journal   (Followers: 35, SJR: 0.442, h-index: 16)
J. of Complex Networks     Hybrid Journal   (Followers: 2, SJR: 1.165, h-index: 5)
J. of Computer-Mediated Communication     Open Access   (Followers: 26, SJR: 2.878, h-index: 80)
J. of Conflict and Security Law     Hybrid Journal   (Followers: 13, SJR: 0.196, h-index: 15)
J. of Consumer Research     Full-text available via subscription   (Followers: 41, SJR: 4.896, h-index: 121)

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Journal Cover Human Molecular Genetics
  Journal Prestige (SJR): 4.288
  Citation Impact (citeScore): 233
  Number of Followers: 8  
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0964-6906 - ISSN (Online) 1460-2083
   Published by Oxford University Press Homepage  [396 journals]
  • Insights into the pathogenesis of dominant retinitis pigmentosa associated
           with a D477G mutation in RPE65
    • Authors: Choi E; Suh S, Sander C, et al.
      Pages: 2225 - 2243
      Abstract: RPE65 is the essential trans–cis isomerase of the classical retinoid (visual) cycle. Mutations in RPE65 give rise to severe retinal dystrophies, most of which are associated with loss of protein function and recessive inheritance. The only known exception is a c.1430G>A (D477G) mutation that gives rise to dominant retinitis pigmentosa with delayed onset and choroidal and macular involvement. Position 477 is distant from functionally critical regions of RPE65. Hence, the mechanism of D477G pathogenicity remains unclear, although protein misfolding and aggregation mechanisms have been suggested. We characterized a D477G knock-in mouse model which exhibited mild age-dependent changes in retinal structure and function. Immunoblot analysis of protein extracts from the eyes of these knock-in mice demonstrated the presence of ubiquitinated RPE65 and reduced RPE65 expression. We observed an accumulation of retinyl esters in the knock-in mice as well as a delay in rhodopsin regeneration kinetics and diminished electroretinography responses, indicative of RPE65 functional impairment induced by the D477G mutation in vivo. However, a cell line expressing D477G RPE65 revealed protein expression levels, cellular localization and retinoid isomerase activity comparable to cells expressing wild-type protein. Structural analysis of an RPE65 chimera suggested that the D477G mutation does not perturb protein folding or tertiary structure. Instead, the mutation generates an aggregation-prone surface that could induce cellular toxicity through abnormal complex formation as suggested by crystal packing analysis. These results indicate that a toxic gain-of-function induced by the D477G RPE65 substitution may play a role in the pathogenesis of this form of dominant retinitis pigmentosa.
      PubDate: Thu, 12 Apr 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy128
      Issue No: Vol. 27, No. 13 (2018)
  • Differential effects of 14-3-3 dimers on Tau phosphorylation, stability
           and toxicity in vivo
    • Authors: Papanikolopoulou K; Grammenoudi S, Samiotaki M, et al.
      Pages: 2244 - 2261
      Abstract: Neurodegenerative dementias collectively known as Tauopathies involve aberrant phosphorylation and aggregation of the neuronal protein Tau. The largely neuronal 14-3-3 proteins are also elevated in the central nervous system (CNS) and cerebrospinal fluid of Tauopathy patients, suggesting functional linkage. We use the simplicity and genetic facility of the Drosophila system to investigate in vivo whether 14-3-3s are causal or synergistic with Tau accumulation in precipitating pathogenesis. Proteomic, biochemical and genetic evidence demonstrate that both Drosophila 14-3-3 proteins interact with human wild-type and mutant Tau on multiple sites irrespective of their phosphorylation state. 14-3-3 dimers regulate steady-state phosphorylation of both wild-type and the R406W mutant Tau, but they are not essential for toxicity of either variant. Moreover, 14-3-3 elevation itself is not pathogenic, but recruitment of dimers on accumulating wild-type Tau increases its steady-state levels ostensibly by occluding access to proteases in a phosphorylation-dependent manner. In contrast, the R406W mutant, which lacks a putative 14-3-3 binding site, responds differentially to elevation of each 14-3-3 isoform. Although excess 14-3-3ζ stabilizes the mutant protein, elevated D14-3-3ɛ has a destabilizing effect probably because of altered 14-3-3 dimer composition. Our collective data demonstrate the complexity of 14-3-3/Tau interactions in vivo and suggest that 14-3-3 attenuation is not appropriate ameliorative treatment of Tauopathies. Finally, we suggest that ‘bystander’ 14-3-3s are recruited by accumulating Tau with the consequences depending on the composition of available dimers within particular neurons and the Tau variant.
      PubDate: Thu, 12 Apr 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy129
      Issue No: Vol. 27, No. 13 (2018)
  • FGF signaling deregulation is associated with early developmental skeletal
           defects in animal models for mucopolysaccharidosis type II (MPSII)
    • Authors: Bellesso S; Salvalaio M, Lualdi S, et al.
      Pages: 2262 - 2275
      Abstract: Skeletal abnormalities represent a major clinical burden in patients affected by the lysosomal storage disorder mucopolysaccharidosis type II (MPSII, OMIM #309900). While extensive research has emphasized the detrimental role of stored glycosaminoglycans (GAGs) in the bone marrow (BM), a limited understanding of primary cellular mechanisms underlying bone defects in MPSII has hampered the development of bone-targeted therapeutic strategies beyond enzyme replacement therapy (ERT). We here investigated the involvement of key signaling pathways related to the loss of iduronate-2-sulfatase activity in two different MPSII animal models, D. rerio and M. musculus. We found that FGF pathway activity is impaired during early stages of bone development in IDS knockout mice and in a newly generated Ids mutant fish. In both models the FGF signaling deregulation anticipated a slow but progressive defect in bone differentiation, regardless of any extensive GAGs storage. We also show that MPSII patient fibroblasts harboring different mutations spanning the IDS gene exhibit perturbed FGF signaling-related markers expression. Our work opens a new venue to discover possible druggable novel key targets in MPSII.
      PubDate: Tue, 10 Apr 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy131
      Issue No: Vol. 27, No. 13 (2018)
  • Noonan syndrome-causing SHP2 mutants impair ERK-dependent chondrocyte
           differentiation during endochondral bone growth
    • Authors: Tajan M; Pernin-Grandjean J, Beton N, et al.
      Pages: 2276 - 2289
      Abstract: Growth retardation is a constant feature of Noonan syndrome (NS) but its physiopathology remains poorly understood. We previously reported that hyperactive NS-causing SHP2 mutants impair the systemic production of insulin‐like growth factor 1 (IGF1) through hyperactivation of the RAS/extracellular signal-regulated kinases (ERK) signalling pathway. Besides endocrine defects, a direct effect of these mutants on growth plate has not been explored, although recent studies have revealed an important physiological role for SHP2 in endochondral bone growth. We demonstrated that growth plate length was reduced in NS mice, mostly due to a shortening of the hypertrophic zone and to a lesser extent of the proliferating zone. These histological features were correlated with decreased expression of early chondrocyte differentiation markers, and with reduced alkaline phosphatase staining and activity, in NS murine primary chondrocytes. Although IGF1 treatment improved growth of NS mice, it did not fully reverse growth plate abnormalities, notably the decreased hypertrophic zone. In contrast, we documented a role of RAS/ERK hyperactivation at the growth plate level since 1) NS-causing SHP2 mutants enhance RAS/ERK activation in chondrocytes in vivo (NS mice) and in vitro (ATDC5 cells) and 2) inhibition of RAS/ERK hyperactivation by U0126 treatment alleviated growth plate abnormalities and enhanced chondrocyte differentiation. Similar effects were obtained by chronic treatment of NS mice with statins. In conclusion, we demonstrated that hyperactive NS-causing SHP2 mutants impair chondrocyte differentiation during endochondral bone growth through a local hyperactivation of the RAS/ERK signalling pathway, and that statin treatment may be a possible therapeutic approach in NS.
      PubDate: Thu, 12 Apr 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy133
      Issue No: Vol. 27, No. 13 (2018)
  • Elevated dual specificity protein phosphatase 4 in cardiomyopathy caused
           by lamin A/C gene mutation is primarily ERK1/2-dependent and its depletion
           improves cardiac function and survival
    • Authors: Choi J; Wu W, Phillips E, et al.
      Pages: 2290 - 2305
      Abstract: Mutations in the lamin A/C gene (LMNA) encoding the nuclear intermediate filament proteins lamins A and C cause a group of tissue-selective diseases, the most common of which is dilated cardiomyopathy (herein referred to as LMNA cardiomyopathy) with variable skeletal muscle involvement. We previously showed that cardiomyocyte-specific overexpression of dual specificity protein phosphatase 4 (DUSP4) is involved in the pathogenesis of LMNA cardiomyopathy. However, how mutations in LMNA activate Dusp4 expression and whether it is necessary for the development of LMNA cardiomyopathy are currently unknown. We now show that female LmnaH222P/H222P mice, a model for LMNA cardiomyopathy, have increased Dusp4 expression and hyperactivation of extracellular signal-regulated kinase (ERK) 1/2 with delayed kinetics relative to male mice, consistent with the sex-dependent delay in the onset and progression of disease. Mechanistically, we show that the H222P amino acid substitution in lamin A enhances its binding to ERK1/2 and increases sequestration at the nuclear envelope. Finally, we show that genetic deletion of Dusp4 has beneficial effects on heart function and prolongs survival in LmnaH222P/H222P mice. These results further establish Dusp4 as a key contributor to the pathogenesis of LMNA cardiomyopathy and a potential target for drug therapy.
      PubDate: Mon, 16 Apr 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy134
      Issue No: Vol. 27, No. 13 (2018)
  • SUMOylation of XRCC1 activated by poly (ADP-ribosyl)ation regulates DNA
    • Authors: Hu L; Chang C, Huang Y, et al.
      Pages: 2306 - 2317
      Abstract: XRCC1 is an essential scaffold protein for base excision repair (BER) and helps to maintain genomic stability. XRCC1 has been indicated as a substrate for small ubiquitin-like modifier modification (SUMOylation); however, how XRCC1 SUMOylation is regulated in cells and how SUMOylated XRCC1 regulates BER activity are not well understood. Here, we show that SUMOylation of XRCC1 is regulated in cells under methyl-methanesulfonate (MMS) treatment and facilitates BER. Poly(ADP-ribose) polymerase 1 (PARP1) is activated by MMS immediately and synthesizes poly(ADP-ribose) (PAR), which in turn promotes recruitment of SUMO E3 TOPORS to XRCC1 and facilitates XRCC1 SUMOylation. A SUMOylation-defective mutant of XRCC1 had lower binding activity for DNA polymerase beta (POLB) and was linked to a lower capacity for repair of MMS-induced DNA damages. Our study therefore identified a pathway in which DNA damage-induced poly(ADP-ribosyl)ation (PARylation) promotes SUMOylation of XRCC1, which leads to more efficient recruitment of POLB to complete BER.
      PubDate: Mon, 16 Apr 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy135
      Issue No: Vol. 27, No. 13 (2018)
  • Identification of novel circulatory microRNA signatures linked to patients
           with ischemic stroke
    • Authors: Vijayan M; Kumar S, Yin X, et al.
      Pages: 2318 - 2329
      Abstract: MicroRNAs (miRNAs) are involved in growth, development, and occurrence and progression of many diseases. MiRNA-mediated post-transcriptional regulation is poorly understood in vascular biology and pathology. The purpose of this is to determine circulatory miRNAs as early detectable peripheral biomarkers in patients with ischemic stroke (IS). MiRNAs expression levels were measured in IS serum samples and healthy controls using Illumina deep sequencing analysis and identified differentially expressed miRNAs. Differentially expressed miRNAs were further validated using SYBR-green-based quantitative real-time PCR (qRT-PCR) assay in postmortem IS brains, lymphoblastoid IS cell lines, oxygen and glucose deprivation/reoxygenation -treated human and mouse neuroblastoma cells, and mouse models of hypoxia and ischemia (HI)-induced stroke. A total of 4656 miRNAs were differentially expressed in IS serum samples relative to healthy controls. Out of 4656 miRNAs, 272 were found to be significantly deregulated in IS patients. Interestingly, we found several novel and previously unreported miRNAs in IS patients relative to healthy controls. Further analyses revealed that some candidate miRNAs and its target genes were involved in the regulation of the stroke. To the best of our knowledge, this is the first study identified potential novel candidate miRNAs in IS serum samples from the residents of rural West Texas. MiRNAs identified in this study could potentially be used as a biomarker and the development of novel therapeutic approaches for stroke. Further studies are necessary to better understand miRNAs-regulated stroke cellular changes.
      PubDate: Wed, 25 Apr 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy136
      Issue No: Vol. 27, No. 13 (2018)
  • Identification of distinct conformations associated with monomers and
           fibril assemblies of mutant huntingtin
    • Authors: Ko J; Isas J, Sabbaugh A, et al.
      Pages: 2330 - 2343
      Abstract: The N-terminal fragments of mutant huntingtin (mHTT) misfold and assemble into oligomers, which ultimately bundle into insoluble fibrils. Conformations unique to various assemblies of mHTT remain unknown. Knowledge on the half-life of various multimeric structures of mHTT is also scarce. Using a panel of four new antibodies named PHP1–4, we have identified new conformations in monomers and assembled structures of mHTT. PHP1 and PHP2 bind to epitopes within the proline-rich domain (PRD), whereas PHP3 and PHP4 interact with motifs formed at the junction of polyglutamine (polyQ) and polyproline (polyP) repeats of HTT. The PHP1- and PHP2-reactive epitopes are exposed in fibrils of mHTT exon1 (mHTTx1) generated from recombinant proteins and mHTT assemblies, which progressively accumulate in the nuclei, cell bodies and neuropils in the brains of HD mouse models. Notably, electron microscopic examination of brain sections of HD mice revealed that PHP1- and PHP2-reactive mHTT assemblies are present in myelin sheath and in vesicle-like structures. Moreover, PHP1 and PHP2 antibodies block seeding and subsequent fibril assembly of mHTTx1 in vitro and in a cell culture model of HD. PHP3 and PHP4 bind to epitopes in full-length and N-terminal fragments of monomeric mHTT and binding diminishes as the mHTTx1 assembles into fibrils. Interestingly, PHP3 and PHP4 also prevent the aggregation of mHTTx1 in vitro highlighting a regulatory function for the polyQ-polyP motifs. These newly detected conformations may affect fibril assembly, stability and intercellular transport of mHTT.
      PubDate: Wed, 18 Apr 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy141
      Issue No: Vol. 27, No. 13 (2018)
  • The c-Abl inhibitor, Radotinib HCl, is neuroprotective in a preclinical
           Parkinson’s disease mouse model
    • Authors: Lee S; Kim S, Park Y, et al.
      Pages: 2344 - 2356
      Abstract: Accumulating evidence suggests that the non-receptor tyrosine kinase c-Abl plays an important role in the progression of Parkinson’s disease (PD) and c-Abl inhibition could be neuroprotective in PD and related α-synucleinopathies. Nilotinib, a c-Abl inhibitor, has shown improved motor and cognitive symptoms in PD patients. However, issues concerning blood–brain barrier (BBB) penetration, lack of selectivity and safety still remain. Radotinib HCl is a selective Bcr-Abl kinase inhibitor that not only effectively access the brain, but also exhibits greater pharmacokinetic properties and safety profiles compared to Nilotinib and other c-Abl inhibitors. Here, we show the neuroprotective efficacy of Radotinib HCl, a brain penetrant c-Abl inhibitor, in a pre-clinical model of PD. Importantly, in vitro studies demonstrate that the treatment of Radotinib HCl protects the α-synuclein preformed fibrils (PFF)-induced neuronal toxicity, reduces the α-synuclein PFF-induced Lewy bodies (LB)/Lewy neurites (LN)-like pathology and inhibits the α-synuclein PFF-induced c-Abl activation in primary cortical neurons. Furthermore, administration of Radotinib HCl inhibits c-Abl activation and prevents dopaminergic neuron loss, neuroinflammation and behavioral deficits following α-synuclein PFF-induced toxicity in vivo. Taken together, our findings indicate that Radotinib HCl has beneficial neuroprotective effects in PD and provides an evidence that selective and brain permeable c-Abl inhibitors can be potential therapeutic agents for the treatment of PD and related α-synucleinopathies.
      PubDate: Fri, 20 Apr 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy143
      Issue No: Vol. 27, No. 13 (2018)
  • A homozygous mutation p.Arg2167Trp in FREM2 causes isolated
    • Authors: Yu Q; Lin B, Xie S, et al.
      Pages: 2357 - 2366
      Abstract: Cryptophthalmos (CO, MIM: 123570) is rare congenital anomalies of eyelid formation, which can occur alone or in combination with multiple congenital anomalies as part of Fraser syndrome (FS) or Manitoba Oculotrichoanal syndrome. Causal mutations have been identified for these syndromes but not in the isolated cases. Here, we described two patients from two unrelated Chinese families: one with unilateral isolated CO, while the other with unilateral CO and renal agenesis. A novel homozygous mutation (c.6499C>T: p.Arg2167Trp) and compound heterozygote mutations (c.15delG; c.6499C>T: p.Arg2167Trp) in FREM2 (NM_172862) were identified for the two patients, respectively. The deletion mutation c.15delG resulted in a frameshift and triggered the nonsense-mediated mRNA decay. For the shared missense mutation, p.Arg2167Trp altered a conserved residue and was predicted to affect protein structure by in silico analysis. Functional analysis revealed that Arg2167Trp mutant decreased its interaction with FRAS1 related extracellular matrix 1 (FREM1) and impaired the function of the FRAS1–FRAS1 related extracellular matrix 1 (FREM2)–FREM1 ternary complex required for normal embryogenesis. Furthermore, considering that mutation (c.5914C>T: p.Glu1972Lys) in FREM2 causes FS, a severe systemic disorder, we also compared these two different missense mutations. Our results showed that p.Arg2167Trp had a weaker effect in interrupting interactions between FREM2 and FREM1 than FS-associated missense mutation p.Glu1972Lys. Overall, our data demonstrate that the homozygous mutation p.Arg2167Trp in FREM2 causes isolated CO, which will facilitate our better understanding of the molecular mechanisms underlying the disease.
      PubDate: Tue, 24 Apr 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy144
      Issue No: Vol. 27, No. 13 (2018)
  • Inositol trisphosphate receptor-mediated Ca2+ signalling stimulates
           mitochondrial function and gene expression in core myopathy patients
    • Authors: Suman M; Sharpe J, Bentham R, et al.
      Pages: 2367 - 2382
      Abstract: Core myopathies are a group of childhood muscle disorders caused by mutations of the ryanodine receptor (RyR1), the Ca2+ release channel of the sarcoplasmic reticulum. These mutations have previously been associated with elevated inositol trisphosphate receptor (IP3R) levels in skeletal muscle myotubes derived from patients. However, the functional relevance and the relationship of IP3R mediated Ca2+ signalling with the pathophysiology of the disease is unclear. It has also been suggested that mitochondrial dysfunction underlies the development of central and diffuse multi-mini-cores, devoid of mitochondrial activity, which is a key pathological consequence of RyR1 mutations. Here we used muscle biopsies of central core and multi-minicore disease patients with RyR1 mutations, as well as cellular and in vivo mouse models of the disease to characterize global cellular and mitochondrial Ca2+ signalling, mitochondrial function and gene expression associated with the disease. We show that RyR1 mutations that lead to the depletion of the channel are associated with increased IP3-mediated nuclear and mitochondrial Ca2+ signals and increased mitochondrial activity. Moreover, western blot and microarray analysis indicated enhanced mitochondrial biogenesis at the transcriptional and protein levels and was reflected in increased mitochondrial DNA content. The phenotype was recapitulated by RYR1 silencing in mouse cellular myotube models. Altogether, these data indicate that remodelling of skeletal muscle Ca2+ signalling following loss of functional RyR1 mediates bioenergetic adaptation.
      PubDate: Wed, 25 Apr 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy149
      Issue No: Vol. 27, No. 13 (2018)
  • A hyperactivating proinflammatory RIPK2 allele associated with early-onset
    • Authors: Jurynec M; Sawitzke A, Beals T, et al.
      Pages: 2383 - 2391
      Abstract: Osteoarthritis (OA) is a common debilitating disease characterized by abnormal remodeling of the cartilage and bone of the articular joint. Ameliorating therapeutics are lacking due to limited understanding of the molecular pathways affecting disease initiation and progression. Notably, although a link between inflammation and overt OA is well established, the role of inflammation as a driver of disease occurrence is highly disputed. We analyzed a family with dominant inheritance of early-onset OA and found that affected individuals harbored a rare variant allele encoding a significant amino acid change (p.Asn104Asp) in the kinase domain of receptor interacting protein kinase 2 (RIPK2), which transduces signals from activated bacterial peptidoglycan sensors through the NF-κB pathway to generate a proinflammatory immune response. Functional analyses of RIPK2 activity in zebrafish embryos indicated that the variant RIPK2104Asp protein is hyperactive in its signaling capacity, with augmented ability to activate the innate immune response and the NF-κB pathway and to promote upregulation of OA-associated genes. Further we show a second allele of RIPK2 linked to an inflammatory disease associated with arthritis also has enhanced activity stimulating the NF-κB pathway. Our studies reveal for the first time the inflammatory response can function as a gatekeeper risk factor for OA.
      PubDate: Thu, 12 Apr 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy132
      Issue No: Vol. 27, No. 13 (2018)
  • A plausibly causal functional lupus-associated risk variant in the
           STAT1–STAT4 locus
    • Authors: Patel Z; Lu X, Miller D, et al.
      Pages: 2392 - 2404
      Abstract: Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1–STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1–STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.
      PubDate: Wed, 18 Apr 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy140
      Issue No: Vol. 27, No. 13 (2018)
  • Transcriptome analysis reveals intermittent fasting-induced genetic
           changes in ischemic stroke
    • Authors: Kim J; Kang S, Mallilankaraman K, et al.
      Pages: 2405 - 2405
      Abstract: Human Molecular Genetics, 2018, 27(9), 1497–1513. doi: 10.1093/hmg/ddy057
      PubDate: Tue, 24 Apr 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy138
      Issue No: Vol. 27, No. 13 (2018)
  • A hyperactivating proinflammatory RIPK2 allele associated with early-onset
    • Authors: Jurynec M; Sawitzke A, Beals T, et al.
      Pages: 2406 - 2406
      Abstract: Human Molecular Genetics, 2018, 27(13), 2383–2391. doi: 10.1093/hmg/ddy132
      PubDate: Wed, 30 May 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy196
      Issue No: Vol. 27, No. 13 (2018)
  • FGF signaling deregulation is associated with early developmental skeletal
           defects in animal models for mucopolysaccharidosis type II (MPSII)
    • Authors: Bellesso S; Salvalaio M, Lualdi S, et al.
      Pages: 2407 - 2407
      Abstract: Human Molecular Genetics, 2018, 27(13), 2262–2275.
      PubDate: Mon, 18 Jun 2018 00:00:00 GMT
      DOI: 10.1093/hmg/ddy208
      Issue No: Vol. 27, No. 13 (2018)
School of Mathematical and Computer Sciences
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