Author
Joshua M. Kuperman
Other affiliations: University of California, Berkeley
Bio: Joshua M. Kuperman is an academic researcher from University of California, San Diego. The author has contributed to research in topics: Diffusion MRI & Medicine. The author has an hindex of 28, co-authored 68 publications receiving 4379 citations. Previous affiliations of Joshua M. Kuperman include University of California, Berkeley.
Papers published on a yearly basis
Papers
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Cornell University1, Yale University2, Washington University in St. Louis3, University of Michigan4, University of Vermont5, University of Colorado Boulder6, Florida International University7, Virginia Commonwealth University8, University of Minnesota9, University of California, San Diego10, Harvard University11
TL;DR: An overview of the imaging procedures of the ABCD study is provided, the basis for their selection and preliminary quality assurance and results that provide evidence for the feasibility and age-appropriateness of procedures and generalizability of findings to the existent literature are provided.
1,114 citations
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Columbia University1, University of Southern California2, University of California, San Diego3, University of California, Davis4, Cornell University5, The Queen's Medical Center6, University of Massachusetts Medical School7, Yale University8, Kennedy Krieger Institute9, Boston Children's Hospital10, Harvard University11
TL;DR: Investigation of relationships between socioeconomic factors and brain morphometry among a cohort of typically developing individuals suggests that income relates most strongly to brain structure among the most disadvantaged children.
Abstract: Socioeconomic disparities are associated with differences in cognitive development. The extent to which this translates to disparities in brain structure is unclear. We investigated relationships between socioeconomic factors and brain morphometry, independently of genetic ancestry, among a cohort of 1,099 typically developing individuals between 3 and 20 years of age. Income was logarithmically associated with brain surface area. Among children from lower income families, small differences in income were associated with relatively large differences in surface area, whereas, among children from higher income families, similar income increments were associated with smaller differences in surface area. These relationships were most prominent in regions supporting language, reading, executive functions and spatial skills; surface area mediated socioeconomic differences in certain neurocognitive abilities. These data imply that income relates most strongly to brain structure among the most disadvantaged children.
939 citations
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TL;DR: It is shown that this method, requiring minimal additional scan time, provides superior accuracy relative to the more commonly used, and more time consuming, field mapping approach, and is also highly computationally efficient, allowing for direct "real-time" implementation on the MRI scanner.
414 citations
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University of California, San Diego1, University of California, Davis2, Scripps Health3, Cornell University4, The Queen's Medical Center5, University of Massachusetts Medical School6, Yale University7, Johns Hopkins University School of Medicine8, Harvard University9, Children's Hospital Los Angeles10, University of Southern California11
TL;DR: This work demonstrates that developmental brain phase can be assessed with much greater precision than has been possible using other biological measures, and reveals for the first time a latent phenotype in the human brain for which maturation timing is tightly controlled.
328 citations
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University of California, San Diego1, J. Craig Venter Institute2, University of Massachusetts Medical School3, University of Washington4, Yale University5, Cornell University6, University of Southern California7, Harvard University8, Boston Children's Hospital9, Johns Hopkins University School of Medicine10, University of California, Davis11
TL;DR: The recruiting and screening of the children are described and a brief overview of the assessments performed, the imaging methods applied, the genetic data produced, and the numbers of cases for whom different data types are available are given.
251 citations
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TL;DR: In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compound optimization and the long-term success of drug candidates.
Abstract: The concept of isosterism between relatively simple chemical entities was originally contemplated by James Moir in 1909, a notion further refined by H. G. Grimm’s hydride displacement law and captured more effectively in the ideas advanced by Irving Langmuir based on experimental observations. Langmuir coined the term “isostere” and, 18 years in advance of its actual isolation and characterization, predicted that the physical properties of the then unknown ketene would resemble those of diazomethane. The emergence of bioisosteres as structurally distinct compounds recognized similarly by biological systems has its origins in a series of studies published byHans Erlenmeyer in the 1930s, who extended earlier work conducted by Karl Landsteiner. Erlenmeyer showed that antibodies were unable to discriminate between phenyl and thienyl rings or O, NH, and CH2 in the context of artificial antigens derived by reacting diazonium ions with proteins, a process that derivatized the ortho position of tyrosine, as summarized in Figure 1 The term “bioisostere” was introduced by Harris Friedman in 1950 who defined it as compounds eliciting a similar biological effect while recognizing that compounds may be isosteric but not necessarily bioisosteric. This notion anticipates that the application of bioisosterism will depend on context, relying much less on physicochemical properties as the underlying principle for biochemical mimicry. Bioisosteres are typically less than exact structural mimetics and are often more alike in biological rather than physical properties. Thus, an effective bioisostere for one biochemical application may not translate to another setting, necessitating the careful selection and tailoring of an isostere for a specific circumstance. Consequently, the design of bioisosteres frequently introduces structural changes that can be beneficial or deleterious depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates. The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering physical properties, reducing or redirecting metabolism, eliminating or modifying toxicophores, and acquiring novel intellectual property. In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compound optimization and the long-term success of drug candidates. Interesting concepts that may have been poorly effective in the context examined are captured, since the ideas may have merit in alternative circumstances. A comprehensive cataloging of bioisosteres is beyond the scope of what will be provided, although a synopsis of relevant isosteres of a particular functionality is summarized in a succinct fashion in several sections. Isosterism has also found productive application in the design and optimization of organocatalysts, and there are several examples in which functional mimicry established initially in a medicinal chemistry setting has been adopted by this community.
2,049 citations
01 Jan 2010
TL;DR: In this paper, the authors show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait, revealing patterns with important implications for genetic studies of common human diseases and traits.
Abstract: Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
1,751 citations
01 Jan 1981
1,737 citations
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RTI International1, University of Maryland, Baltimore2, University of the West Indies3, University of California, Berkeley4, Harvard University5, Georgia State University6, Brigham and Women's Hospital7, University of Pennsylvania8, American University9, World Bank Group10, University College London11
TL;DR: Recent scientific progress and global commitments to early childhood development are examined, with new neuroscientific evidence linking early adversity and nurturing care with brain development and function throughout the life course.
1,534 citations
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TL;DR: Predictive genetic testing and findings of neuroimaging studies show that Huntington's disease is emerging as a model for strategies to develop therapeutic interventions, not only to slow progression of manifest disease but also to delay, or ideally prevent, its onset.
Abstract: Huntington's disease is a progressive, fatal, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene, which encodes an abnormally long polyglutamine repeat in the huntingtin protein. Huntington's disease has served as a model for the study of other more common neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. These disorders all share features including: delayed onset; selective neuronal vulnerability, despite widespread expression of disease-related proteins during the whole lifetime; abnormal protein processing and aggregation; and cellular toxic effects involving both cell autonomous and cell-cell interaction mechanisms. Pathogenic pathways of Huntington's disease are beginning to be unravelled, offering targets for treatments. Additionally, predictive genetic testing and findings of neuroimaging studies show that, as in some other neurodegenerative disorders, neurodegeneration in affected individuals begins many years before onset of diagnosable signs and symptoms of Huntington's disease, and it is accompanied by subtle cognitive, motor, and psychiatric changes (so-called prodromal disease). Thus, Huntington's disease is also emerging as a model for strategies to develop therapeutic interventions, not only to slow progression of manifest disease but also to delay, or ideally prevent, its onset.
1,394 citations