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  • 1
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 1994
    In:  Nature Vol. 368, No. 6469 ( 1994-3), p. 298-298
    In: Nature, Springer Science and Business Media LLC, Vol. 368, No. 6469 ( 1994-3), p. 298-298
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 1994
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  • 2
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 1999
    In:  Proceedings of the National Academy of Sciences Vol. 96, No. 14 ( 1999-07-06), p. 8283-8288
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 96, No. 14 ( 1999-07-06), p. 8283-8288
    Abstract: Corticotropin-releasing hormone (CRH) is a central regulator of the hormonal stress response, causing stimulation of corticotropin and glucocorticoid secretion. CRH is also widely believed to mediate stress-induced behaviors, implying a broader, integrative role for the hormone in the psychological stress response. Mice lacking the CRH gene exhibit normal stress-induced behavior that is specifically blocked by a CRH type 1 receptor antagonist. The other known mammalian ligand for CRH receptors is urocortin. Normal and CRH-deficient mice have an identical distribution of urocortin mRNA, which is confined to the region of the Edinger–Westphal nucleus, and is absent from regions known to mediate stress-related behaviors. Since the Edinger–Westphal nucleus is not known to project to any brain regions believed to play a role in anxiety-like behavior, an entirely different pathway must be postulated for urocortin in the Edinger–Westphal nucleus to mediate these behaviors in CRH-deficient mice. Alternatively, an unidentified CRH-like molecule other than CRH or urocortin, acting through the CRH receptors in brain regions believed to mediate stress-induced behaviors, may mediate the behavioral response to stress, either alone or in concert with CRH.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1999
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 3
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 1995
    In:  Nature Vol. 373, No. 6513 ( 1995-2), p. 427-432
    In: Nature, Springer Science and Business Media LLC, Vol. 373, No. 6513 ( 1995-2), p. 427-432
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 1995
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
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  • 4
    Online Resource
    Online Resource
    Wiley ; 1996
    In:  Annals of the New York Academy of Sciences Vol. 780, No. 1 ( 1996-06), p. 49-59
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 780, No. 1 ( 1996-06), p. 49-59
    Abstract: The generation of transgenic mice by introduction of intact or altered genes into the pronuclei of fertilized oocytes has proven a powerful tool in elucidating the consequences of ectopic or tissue‐appropriate overproduction of a given gene product; in defining DNA elements responsible for gene‐specific patterns of temporal, spatial, and regulated transcription; and in targeted oncogenesis for the development of cell culture lines for detailed in vitro study. This technology, however, has had limited success in addressing the role and essential function of specific peptides in the intact organism, except in the circumstance in which dominant negative alleles, capable of abrogating function of the normal allele, are available. 1,2 With the establishment of embryonic stem (ES) cell culture systems amenable to in vitro manipulation for introduction of mutated genes, methods for selection of relatively rare homologous recombination events, and most importantly, the sustained capacity of these ES cells to contribute to the germline of chimeric mice, a method of addressing the consequences of loss of gene function has emerged. 3,5 Targeted gene inactivation in ES cells with subsequent generation of deficient mice yields inheritable, complete loss of function at all stages of development and in all tissues. This is an advantage when assessing ontogenic importance, ability of interacting systems to compensate for loss of function, and the effects of chronic deficiency. These factors can also impair whole‐organism analysis of function, inasmuch as chronic deficiency may allow up‐regulation of compensatory systems, masking the in vivo function of the mutation, and global deficiency may make characterization at a specific site of synthesis difficult to determine. Most severely, loss of expression at all stages of development may lead to organism inviability.
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 1996
    detail.hit.zdb_id: 2834079-6
    detail.hit.zdb_id: 211003-9
    detail.hit.zdb_id: 2071584-5
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  • 5
    Online Resource
    Online Resource
    Wiley ; 1995
    In:  Annals of the New York Academy of Sciences Vol. 771, No. 1 ( 1995-12), p. 293-300
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 771, No. 1 ( 1995-12), p. 293-300
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 1995
    detail.hit.zdb_id: 2834079-6
    detail.hit.zdb_id: 211003-9
    detail.hit.zdb_id: 2071584-5
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  • 6
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 1999
    In:  Proceedings of the National Academy of Sciences Vol. 96, No. 12 ( 1999-06-08), p. 7093-7097
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 96, No. 12 ( 1999-06-08), p. 7093-7097
    Abstract: Traditionally, the adrenal gland has been considered an important endocrine component of the pathway to inhibit acute inflammation via hypothalamic corticotropin-releasing hormone (CRH)-mediated secretion of glucocorticoid. Immunoreactive CRH found in inflamed tissues is a potent proinflammatory factor. Using genetic and pharmacological models of CRH deficiency, we now show that CRH deficiency unmasks a major proinflammatory effect of epinephrine secreted from the adrenal medulla. Together, epinephrine and peripheral CRH stimulate inflammation, and glucocorticoid acts as a counterbalancing force in this regard. Our findings suggest that stimulation of the acute inflammatory response should be included with the other “fight-or-flight” actions of epinephrine.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1999
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    detail.hit.zdb_id: 1461794-8
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  • 7
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 12 ( 2022-03-22)
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 12 ( 2022-03-22)
    Abstract: Reductions in antimicrobial consumption are needed to mitigate the burden of antimicrobial resistance. Vaccines may have an important role to play in reducing antimicrobial consumption by preventing infections for which treatment is often prescribed, whether appropriately or inappropriately. However, limited understanding of the volume of antimicrobial treatment attributable to specific pathogens—and to viruses, in particular—presently hinders efforts to prioritize vaccines with the greatest potential to reduce antimicrobial consumption. In a double-blind trial undertaken across 11 countries, infants born to mothers who were randomized to receive an experimental vaccine against respiratory syncytial virus (RSV) experienced 12.9% (95% CI: 1.3 to 23.1%) lower incidence of antimicrobial prescribing over the first 3 mo of life than infants whose mothers were randomized to receive placebo. Vaccine efficacy against antimicrobial prescriptions associated with acute lower respiratory tract infections (LRTIs) was 16.9% (95% CI: 1.4 to 29.4%). Over the first 3 mo of life, maternal vaccination prevented 3.6 antimicrobial prescription courses for every 100 infants born in high-income countries and 5.1 courses per 100 infants in low- and middle-income countries, representing 20.2 and 10.9% of all antimicrobial prescribing in these settings, respectively. While LRTI episodes accounted for 69 to 73% of all antimicrobial prescribing prevented by maternal vaccination, striking vaccine efficacy (71.3% [95% CI: 28.1 to 88.6%]) was also observed against acute otitis media–associated antimicrobial prescription among infants in high-income countries. Our findings implicate RSV as a cause of substantial volumes of antimicrobial prescribing among young infants and demonstrate the potential for prevention of such prescribing through use of maternal vaccines against RSV.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
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  • 8
    In: Nature, Springer Science and Business Media LLC, Vol. 600, No. 7889 ( 2021-12-16), p. 472-477
    Abstract: The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 9
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 378, No. 6615 ( 2022-10-07)
    Abstract: Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century. Expanse of SARS-CoV-2 sequencing capacity in Africa. ( A ) African countries (shaded in gray) and institutions (red circles) with on-site sequencing facilities that are capable of producing SARS-CoV-2 whole genomes locally. ( B ) The number of SARS-CoV-2 genomes produced per country and the proportion of those genomes that were produced locally, regionally within Africa, or abroad. ( C ) Decreased turnaround time of sequencing output in Africa to an almost real-time release of genomic data.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2022
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  • 10
    In: Nature, Springer Science and Business Media LLC, Vol. 607, No. 7917 ( 2022-07-07), p. 97-103
    Abstract: Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care 1 or hospitalization 2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling ( IL10RB and PLSCR1 ), leucocyte differentiation ( BCL11A ) and blood-type antigen secretor status ( FUT2 ). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase ( ATP11A ), and increased expression of a mucin ( MUC1 )—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules ( SELE , ICAM5 and CD209 ) and the coagulation factor F8 , all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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