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  • Proceedings of the National Academy of Sciences  (28)
  • 1
    Online Resource
    Online Resource
    Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 14 ( 2017-04-04)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 14 ( 2017-04-04)
    Abstract: The neonatal crystallizable fragment receptor (FcRn) is responsible for maintaining the long half-life and high levels of the two most abundant circulating proteins, albumin and IgG. In the latter case, the protective mechanism derives from FcRn binding to IgG in the weakly acidic environment contained within endosomes of hematopoietic and parenchymal cells, whereupon IgG is diverted from degradation in lysosomes and is recycled. The cellular location and mechanism by which FcRn protects albumin are partially understood. Here we demonstrate that mice with global or liver-specific FcRn deletion exhibit hypoalbuminemia, albumin loss into the bile, and increased albumin levels in the hepatocyte. In vitro models with polarized cells illustrate that FcRn mediates basal recycling and bidirectional transcytosis of albumin and uniquely determines the physiologic release of newly synthesized albumin into the basal milieu. These properties allow hepatic FcRn to mediate albumin delivery and maintenance in the circulation, but they also enhance sensitivity to the albumin-bound hepatotoxin, acetaminophen (APAP). As such, global or liver-specific deletion of FcRn results in resistance to APAP-induced liver injury through increased albumin loss into the bile and increased intracellular albumin scavenging of reactive oxygen species. Further, protection from injury is achieved by pharmacologic blockade of FcRn–albumin interactions with monoclonal antibodies or peptide mimetics, which cause hypoalbuminemia, biliary loss of albumin, and increased intracellular accumulation of albumin in the hepatocyte. Together, these studies demonstrate that the main function of hepatic FcRn is to direct albumin into the circulation, thereby also increasing hepatocyte sensitivity to toxicity.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1618291114
    RVK:
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    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 2
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    Reply to De Coster et al.: Exploring the complexity of ecosystem–human health relationships
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 18 ( 2014-05-06)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 18 ( 2014-05-06)
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1402671111
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 3
    Online Resource
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    Human health impacts of ecosystem alteration
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 47 ( 2013-11-19), p. 18753-18760
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 47 ( 2013-11-19), p. 18753-18760
    Abstract: Human activity is rapidly transforming most of Earth’s natural systems. How this transformation is impacting human health, whose health is at greatest risk, and the magnitude of the associated disease burden are relatively new subjects within the field of environmental health. We discuss what is known about the human health implications of changes in the structure and function of natural systems and propose that these changes are affecting human health in a variety of important ways. We identify several gaps and limitations in the research that has been done to date and propose a more systematic and comprehensive approach to applied research in this field. Such efforts could lead to a more robust understanding of the human health impacts of accelerating environmental change and inform decision making in the land-use planning, environmental conservation, and public health policy realms.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1218656110
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 4
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    Albendazole and antibiotics synergize to deliver short-course anti- Wolbachia curative treatments in preclinical models of filariasis
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 45 ( 2017-11-07)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 45 ( 2017-11-07)
    Abstract: Elimination of filariasis requires a macrofilaricide treatment that can be delivered within a 7-day period. Here we have identified a synergy between the anthelmintic albendazole (ABZ) and drugs depleting the filarial endosymbiont Wolbachia , a proven macrofilaricide target, which reduces treatment from several weeks to 7 days in preclinical models. ABZ had negligible effects on Wolbachia but synergized with minocycline or rifampicin (RIF) to deplete symbionts, block embryogenesis, and stop microfilariae production. Greater than 99% Wolbachia depletion following 7-day combination of RIF+ABZ also led to accelerated macrofilaricidal activity. Thus, we provide preclinical proof-of-concept of treatment shortening using antibiotic+ABZ combinations to deliver anti- Wolbachia sterilizing and macrofilaricidal effects. Our data are of immediate public health importance as RIF+ABZ are registered drugs and thus immediately implementable to deliver a 1-wk macrofilaricide. They also suggest that novel, more potent anti- Wolbachia drugs under development may be capable of delivering further treatment shortening, to days rather than weeks, if combined with benzimidazoles.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1710845114
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 5
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    Anatomically interpretable deep learning of brain age captures domain-specific cognitive impairment
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 2 ( 2023-01-10)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 2 ( 2023-01-10)
    Abstract: The gap between chronological age (CA) and biological brain age, as estimated from magnetic resonance images (MRIs), reflects how individual patterns of neuroanatomic aging deviate from their typical trajectories. MRI-derived brain age (BA) estimates are often obtained using deep learning models that may perform relatively poorly on new data or that lack neuroanatomic interpretability. This study introduces a convolutional neural network (CNN) to estimate BA after training on the MRIs of 4,681 cognitively normal (CN) participants and testing on 1,170 CN participants from an independent sample. BA estimation errors are notably lower than those of previous studies. At both individual and cohort levels, the CNN provides detailed anatomic maps of brain aging patterns that reveal sex dimorphisms and neurocognitive trajectories in adults with mild cognitive impairment (MCI, N  = 351) and Alzheimer’s disease (AD, N  = 359). In individuals with MCI (54% of whom were diagnosed with dementia within 10.9 y from MRI acquisition), BA is significantly better than CA in capturing dementia symptom severity, functional disability, and executive function. Profiles of sex dimorphism and lateralization in brain aging also map onto patterns of neuroanatomic change that reflect cognitive decline. Significant associations between BA and neurocognitive measures suggest that the proposed framework can map, systematically, the relationship between aging-related neuroanatomy changes in CN individuals and in participants with MCI or AD. Early identification of such neuroanatomy changes can help to screen individuals according to their AD risk.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2214634120
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 6
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    De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 5 ( 2020-02-04), p. 2560-2569
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 5 ( 2020-02-04), p. 2560-2569
    Abstract: De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains 〈 1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability ( h 2 ), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1902766117
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 7
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    Morphometricity as a measure of the neuroanatomical signature of a trait
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 39 ( 2016-09-27)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 39 ( 2016-09-27)
    Abstract: Complex physiological and behavioral traits, including neurological and psychiatric disorders, often associate with distributed anatomical variation. This paper introduces a global metric, called morphometricity, as a measure of the anatomical signature of different traits. Morphometricity is defined as the proportion of phenotypic variation that can be explained by macroscopic brain morphology. We estimate morphometricity via a linear mixed-effects model that uses an anatomical similarity matrix computed based on measurements derived from structural brain MRI scans. We examined over 3,800 unique MRI scans from nine large-scale studies to estimate the morphometricity of a range of phenotypes, including clinical diagnoses such as Alzheimer’s disease, and nonclinical traits such as measures of cognition. Our results demonstrate that morphometricity can provide novel insights about the neuroanatomical correlates of a diverse set of traits, revealing associations that might not be detectable through traditional statistical techniques.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1604378113
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 8
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    Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 12 ( 2013-03-19), p. 4768-4773
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 12 ( 2013-03-19), p. 4768-4773
    Abstract: Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism ( MACROD2 ), development ( NEDD4 ), and mental retardation ( UBE2A ) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1216206110
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 9
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    Characterization of HPV and host genome interactions in primary head and neck cancers
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 43 ( 2014-10-28), p. 15544-15549
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 43 ( 2014-10-28), p. 15544-15549
    Abstract: Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1416074111
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 10
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    Statistical tests and identifiability conditions for pooling and analyzing multisite datasets
    Proceedings of the National Academy of Sciences ; 2018
    In:  Proceedings of the National Academy of Sciences Vol. 115, No. 7 ( 2018-02-13), p. 1481-1486
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 115, No. 7 ( 2018-02-13), p. 1481-1486
    Abstract: When sample sizes are small, the ability to identify weak (but scientifically interesting) associations between a set of predictors and a response may be enhanced by pooling existing datasets. However, variations in acquisition methods and the distribution of participants or observations between datasets, especially due to the distributional shifts in some predictors, may obfuscate real effects when datasets are combined. We present a rigorous statistical treatment of this problem and identify conditions where we can correct the distributional shift. We also provide an algorithm for the situation where the correction is identifiable. We analyze various properties of the framework for testing model fit, constructing confidence intervals, and evaluating consistency characteristics. Our technical development is motivated by Alzheimer’s disease (AD) studies, and we present empirical results showing that our framework enables harmonizing of protein biomarkers, even when the assays across sites differ. Our contribution may, in part, mitigate a bottleneck that researchers face in clinical research when pooling smaller sized datasets and may offer benefits when the subjects of interest are difficult to recruit or when resources prohibit large single-site studies.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1719747115
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2018
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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