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  • Proceedings of the National Academy of Sciences  (12)
  • 1
    Online Resource
    Online Resource
    A role for NPY-NPY2R signaling in albuminuric kidney disease
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 27 ( 2020-07-07), p. 15862-15873
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 27 ( 2020-07-07), p. 15862-15873
    Abstract: Albuminuria is an independent risk factor for the progression to end-stage kidney failure, cardiovascular morbidity, and premature death. As such, discovering signaling pathways that modulate albuminuria is desirable. Here, we studied the transcriptomes of podocytes, key cells in the prevention of albuminuria, under diabetic conditions. We found that Neuropeptide Y (NPY) was significantly down-regulated in insulin-resistant vs. insulin-sensitive mouse podocytes and in human glomeruli of patients with early and late-stage diabetic nephropathy, as well as other nondiabetic glomerular diseases. This contrasts with the increased plasma and urinary levels of NPY that are observed in such conditions. Studying NPY-knockout mice, we found that NPY deficiency in vivo surprisingly reduced the level of albuminuria and podocyte injury in models of both diabetic and nondiabetic kidney disease. In vitro, podocyte NPY signaling occurred via the NPY2 receptor (NPY2R), stimulating PI3K, MAPK, and NFAT activation. Additional unbiased proteomic analysis revealed that glomerular NPY-NPY2R signaling predicted nephrotoxicity, modulated RNA processing, and inhibited cell migration. Furthermore, pharmacologically inhibiting the NPY2R in vivo significantly reduced albuminuria in adriamycin-treated glomerulosclerotic mice. Our findings suggest a pathogenic role of excessive NPY-NPY2R signaling in the glomerulus and that inhibiting NPY-NPY2R signaling in albuminuric kidney disease has therapeutic potential.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2004651117
    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
    SSG: 12
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  • 2
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    Online Resource
    Prenatal and early-life exposure to the Great Chinese Famine increased the risk of tuberculosis in adulthood across two generations
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 44 ( 2020-11-03), p. 27549-27555
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 44 ( 2020-11-03), p. 27549-27555
    Abstract: Global food security is a major driver of population health, and food system collapse may have complex and long-lasting effects on health outcomes. We examined the effect of prenatal exposure to the Great Chinese Famine (1958–1962)—the largest famine in human history—on pulmonary tuberculosis (PTB) across consecutive generations in a major center of ongoing transmission in China. We analyzed 〉 1 million PTB cases diagnosed between 2005 and 2018 in Sichuan Province using age–period–cohort analysis and mixed-effects metaregression to estimate the effect of the famine on PTB risk in the directly affected birth cohort (F1) and their likely offspring (F2). The analysis was repeated on certain sexually transmitted and blood-borne infections (STBBI) to explore potential mechanisms of the intergenerational effects. A substantial burden of active PTB in the exposed F1 cohort and their offspring was attributable to the Great Chinese Famine, with more than 12,000 famine-attributable active PTB cases ( 〉 1.23% of all cases reported between 2005 and 2018). An interquartile range increase in famine intensity resulted in a 6.53% (95% confidence interval [CI]: 1.19–12.14%) increase in the ratio of observed to expected incidence rate (incidence rate ratio, IRR) in the absence of famine in F1, and an 8.32% (95% CI: 0.59–16.6%) increase in F2 IRR. Increased risk of STBBI was also observed in F2. Prenatal and early-life exposure to malnutrition may increase the risk of active PTB in the exposed generation and their offspring, with the intergenerational effect potentially due to both within-household transmission and increases in host susceptibility.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2008336117
    RVK:
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    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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  • 3
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    Online Resource
    The evening complex integrates photoperiod signals to control flowering in rice
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 26 ( 2022-06-28)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 26 ( 2022-06-28)
    Abstract: Plants use photoperiodism to activate flowering in response to a particular daylength. In rice, flowering is accelerated in short-day conditions, and even a brief exposure to light during the dark period (night-break) is sufficient to delay flowering. Although many of the genes involved in controlling flowering in rice have been uncovered, how the long- and short-day flowering pathways are integrated, and the mechanism of photoperiod perception is not understood. While many of the signaling components controlling photoperiod-activated flowering are conserved between Arabidopsis and rice, flowering in these two systems is activated by opposite photoperiods. Here we establish that photoperiodism in rice is controlled by the evening complex (EC). We show that mutants in the EC genes LUX ARRYTHMO ( LUX ) and EARLY FLOWERING3 ( ELF3 ) paralogs abolish rice flowering. We also show that the EC directly binds and suppresses the expression of flowering repressors, including PRR37 and Ghd7 . We further demonstrate that light acts via phyB to cause a rapid and sustained posttranslational modification of ELF3-1. Our results suggest a mechanism by which the EC is able to control both long- and short-day flowering pathways.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2122582119
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 4
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    Online Resource
    Genetic variants linked to education predict longevity
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 47 ( 2016-11-22), p. 13366-13371
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 47 ( 2016-11-22), p. 13366-13371
    Abstract: Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members’ polygenic profile score for education to predict their parents’ longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total n deaths = 79,702) and ∼2.4% lower risk for fathers (total n deaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1605334113
    RVK:
    TA 1000
    RVK:
    WA 15000
    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
    SSG: 11
    SSG: 12
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  • 5
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    Online Resource
    Country-level gender inequality is associated with structural differences in the brains of women and men
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 20 ( 2023-05-16)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 20 ( 2023-05-16)
    Abstract: Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women’s worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women’s brains and provide initial evidence for neuroscience-informed policies for gender equality.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2218782120
    RVK:
    TA 1000
    RVK:
    WA 15000
    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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    Scientific basis for safely shutting in the Macondo Well after the April 20, 2010 Deepwater Horizon blowout
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 50 ( 2012-12-11), p. 20268-20273
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 50 ( 2012-12-11), p. 20268-20273
    Abstract: As part of the government response to the Deepwater Horizon blowout, a Well Integrity Team evaluated the geologic hazards of shutting in the Macondo Well at the seafloor and determined the conditions under which it could safely be undertaken. Of particular concern was the possibility that, under the anticipated high shut-in pressures, oil could leak out of the well casing below the seafloor. Such a leak could lead to new geologic pathways for hydrocarbon release to the Gulf of Mexico. Evaluating this hazard required analyses of 2D and 3D seismic surveys, seafloor bathymetry, sediment properties, geophysical well logs, and drilling data to assess the geological, hydrological, and geomechanical conditions around the Macondo Well. After the well was successfully capped and shut in on July 15, 2010, a variety of monitoring activities were used to assess subsurface well integrity. These activities included acquisition of wellhead pressure data, marine multichannel seismic profiles, seafloor and water-column sonar surveys, and wellhead visual/acoustic monitoring. These data showed that the Macondo Well was not leaking after shut in, and therefore, it could remain safely shut until reservoir pressures were suppressed (killed) with heavy drilling mud and the well was sealed with cement.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1115847109
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 7
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    Online Resource
    A polymorphism within a conserved β 1 -adrenergic receptor motif alters cardiac function and β-blocker response in human heart failure
    Proceedings of the National Academy of Sciences ; 2006
    In:  Proceedings of the National Academy of Sciences Vol. 103, No. 30 ( 2006-07-25), p. 11288-11293
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 103, No. 30 ( 2006-07-25), p. 11288-11293
    Abstract: Heterogeneity of heart failure (HF) phenotypes indicates contributions from underlying common polymorphisms. We considered polymorphisms in the β 1 -adrenergic receptor (β 1 AR), a β-blocker target, as candidate pharmacogenomic loci. Transfected cells, genotyped human nonfailing and failing ventricles, and a clinical trial were used to ascertain phenotype and mechanism. In nonfailing and failing isolated ventricles, β 1 -Arg-389 had respective 2.8 ± 0.3- and 4.3 ± 2.1-fold greater agonist-promoted contractility vs. β 1 -Gly-389, defining enhanced physiologic coupling under relevant conditions of endogenous expression and HF. The β-blocker bucindolol was an inverse agonist in failing Arg, but not Gly, ventricles, without partial agonist activity at either receptor; carvedilol was a genotype-independent neutral antagonist. In transfected cells, bucindolol antagonized agonist-stimulated cAMP, with a greater absolute decrease observed for Arg-389 (435 ± 80 vs. 115 ± 23 fmol per well). Potential pathophysiologic correlates were assessed in a placebo-controlled trial of bucindolol in 1,040 HF patients. No outcome was associated with genotype in the placebo group, indicating little impact on the natural course of HF. However, the Arg-389 homozygotes treated with bucindolol had an age-, sex-, and race-adjusted 38% reduction in mortality ( P = 0.03) and 34% reduction in mortality or hospitalization ( P = 0.004) vs. placebo. In contrast, Gly-389 carriers had no clinical response to bucindolol compared with placebo. Those with Arg-389 and high baseline norepinephrine levels trended toward improved survival, but no advantage with this allele and exaggerated sympatholysis was identified. We conclude that β 1 AR-389 variation alters signaling in multiple models and affects the β-blocker therapeutic response in HF and, thus, might be used to individualize treatment of the syndrome.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0509937103
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2006
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 8
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    HLA tapasin independence: broader peptide repertoire and HIV control
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 45 ( 2020-11-10), p. 28232-28238
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 45 ( 2020-11-10), p. 28232-28238
    Abstract: Human leukocyte antigen (HLA) class I allotypes vary in their ability to present peptides in the absence of tapasin, an essential component of the peptide loading complex. We quantified tapasin dependence of all allotypes that are common in European and African Americans ( n = 97), which revealed a broad continuum of values. Ex vivo examination of cytotoxic T cell responses to the entire HIV-1 proteome from infected subjects indicates that tapasin-dependent allotypes present a more limited set of distinct peptides than do tapasin-independent allotypes, data supported by computational predictions. This suggests that variation in tapasin dependence may impact the strength of the immune responses by altering peptide repertoire size. In support of this model, we observed that individuals carrying HLA class I genotypes characterized by greater tapasin independence progress more slowly to AIDS and maintain lower viral loads, presumably due to increased breadth of peptide presentation. Thus, tapasin dependence level, like HLA zygosity, may serve as a means to restrict or expand breadth of the HLA-I peptide repertoire across humans, ultimately influencing immune responses to pathogens and vaccines.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2013554117
    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
    SSG: 12
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  • 9
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    Genetic variation associated with euphorigenic effects of d -amphetamine is associated with diminished risk for schizophrenia and attention deficit hyperactivity disorder
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 16 ( 2014-04-22), p. 5968-5973
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 16 ( 2014-04-22), p. 5968-5973
    Abstract: Here, we extended our findings from a genome-wide association study of the euphoric response to d -amphetamine in healthy human volunteers by identifying enrichment between SNPs associated with response to d -amphetamine and SNPs associated with psychiatric disorders. We found that SNPs nominally associated ( P ≤ 0.05 and P ≤ 0.01) with schizophrenia and attention deficit hyperactivity disorder were also nominally associated with d -amphetamine response. Furthermore, we found that the source of this enrichment was an excess of alleles that increased sensitivity to the euphoric effects of d -amphetamine and decreased susceptibility to schizophrenia and attention deficit hyperactivity disorder. In contrast, three negative control phenotypes (height, inflammatory bowel disease, and Parkinson disease) did not show this enrichment. Taken together, our results suggest that alleles identified using an acute challenge with a dopaminergic drug in healthy individuals can be used to identify alleles that confer risk for psychiatric disorders commonly treated with dopaminergic agonists and antagonists. More importantly, our results show the use of the enrichment approach as an alternative to stringent standards for genome-wide significance and suggest a relatively novel approach to the analysis of small cohorts in which intermediate phenotypes have been measured.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1318810111
    RVK:
    TA 1000
    RVK:
    WA 15000
    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
    SSG: 12
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  • 10
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    Genomic correlates of clinical outcome in advanced prostate cancer
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 23 ( 2019-06-04), p. 11428-11436
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 23 ( 2019-06-04), p. 11428-11436
    Abstract: Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor ( AR ) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1 , AR , and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1902651116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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