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  • 1
    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
    Kurzfassung: 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.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    RVK:
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    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2014
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    Online-Ressource
    Online-Ressource
    American Association for the Advancement of Science (AAAS) ; 2003
    In:  Science Vol. 302, No. 5648 ( 2003-11-14), p. 1157-1157
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 302, No. 5648 ( 2003-11-14), p. 1157-1157
    Materialart: Online-Ressource
    ISSN: 0036-8075 , 1095-9203
    RVK:
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    Sprache: Englisch
    Verlag: American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 2003
    ZDB Id: 128410-1
    ZDB Id: 2066996-3
    ZDB Id: 2060783-0
    SSG: 11
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 378, No. 6615 ( 2022-10-07)
    Kurzfassung: 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.
    Materialart: Online-Ressource
    ISSN: 0036-8075 , 1095-9203
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    Sprache: Englisch
    Verlag: American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 2022
    ZDB Id: 128410-1
    ZDB Id: 2066996-3
    ZDB Id: 2060783-0
    SSG: 11
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 4 ( 2023-04-19), p. 1648-1661
    Kurzfassung: Different neurological manifestations of coronavirus disease 2019 (COVID-19) in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicentre observational study using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) cohort across 1507 sites worldwide from 30 January 2020 to 25 May 2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models. Overall, 161 239 patients (158 267 adults; 2972 children) hospitalized with COVID-19 and assessed for neurological manifestations and complications were included. In adults and children, the most frequent neurological manifestations at admission were fatigue (adults: 37.4%; children: 20.4%), altered consciousness (20.9%; 6.8%), myalgia (16.9%; 7.6%), dysgeusia (7.4%; 1.9%), anosmia (6.0%; 2.2%) and seizure (1.1%; 5.2%). In adults, the most frequent in-hospital neurological complications were stroke (1.5%), seizure (1%) and CNS infection (0.2%). Each occurred more frequently in intensive care unit (ICU) than in non-ICU patients. In children, seizure was the only neurological complication to occur more frequently in ICU versus non-ICU (7.1% versus 2.3%, P & lt; 0.001). Stroke prevalence increased with increasing age, while CNS infection and seizure steadily decreased with age. There was a dramatic decrease in stroke over time during the pandemic. Hypertension, chronic neurological disease and the use of extracorporeal membrane oxygenation were associated with increased risk of stroke. Altered consciousness was associated with CNS infection, seizure and stroke. All in-hospital neurological complications were associated with increased odds of death. The likelihood of death rose with increasing age, especially after 25 years of age. In conclusion, adults and children have different neurological manifestations and in-hospital complications associated with COVID-19. Stroke risk increased with increasing age, while CNS infection and seizure risk decreased with age.
    Materialart: Online-Ressource
    ISSN: 0006-8950 , 1460-2156
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    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2023
    ZDB Id: 1474117-9
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 362, No. 6419 ( 2018-12-07), p. 1161-1164
    Kurzfassung: We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F , and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.
    Materialart: Online-Ressource
    ISSN: 0036-8075 , 1095-9203
    RVK:
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    Sprache: Englisch
    Verlag: American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 2018
    ZDB Id: 128410-1
    ZDB Id: 2066996-3
    ZDB Id: 2060783-0
    SSG: 11
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 376, No. 6597 ( 2022-06-03), p. 1074-1079
    Kurzfassung: Nucleoside sulfamates hijack a step in protein biosynthesis to inhibit malaria infection.
    Materialart: Online-Ressource
    ISSN: 0036-8075 , 1095-9203
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 2022
    ZDB Id: 128410-1
    ZDB Id: 2066996-3
    ZDB Id: 2060783-0
    SSG: 11
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 373, No. 6556 ( 2021-08-13), p. 808-812
    Kurzfassung: Total daily energy expenditure (“total expenditure”) reflects daily energy needs and is a critical variable in human health and physiology, but its trajectory over the life course is poorly studied. We analyzed a large, diverse database of total expenditure measured by the doubly labeled water method for males and females aged 8 days to 95 years. Total expenditure increased with fat-free mass in a power-law manner, with four distinct life stages. Fat-free mass–adjusted expenditure accelerates rapidly in neonates to ~50% above adult values at ~1 year; declines slowly to adult levels by ~20 years; remains stable in adulthood (20 to 60 years), even during pregnancy; then declines in older adults. These changes shed light on human development and aging and should help shape nutrition and health strategies across the life span.
    Materialart: Online-Ressource
    ISSN: 0036-8075 , 1095-9203
    RVK:
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    Sprache: Englisch
    Verlag: American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 2021
    ZDB Id: 128410-1
    ZDB Id: 2066996-3
    ZDB Id: 2060783-0
    SSG: 11
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 378, No. 6622 ( 2022-11-25), p. 909-915
    Kurzfassung: A large survey measures human physiological water requirements in varying situations.
    Materialart: Online-Ressource
    ISSN: 0036-8075 , 1095-9203
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 2022
    ZDB Id: 128410-1
    ZDB Id: 2066996-3
    ZDB Id: 2060783-0
    SSG: 11
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 27, No. 29 ( 2007-07-18), p. 7869-7878
    Kurzfassung: Transgenic R6/2 mice carrying the Huntington's disease (HD) mutation show disrupted circadian rhythms that worsen as the disease progresses. By 15 weeks of age, their abnormal circadian behavior mirrors that seen in HD patients and is accompanied by dysregulated clock gene expression in the circadian pacemaker, the suprachiasmatic nucleus (SCN). We found, however, that the electrophysiological output of the SCN assayed in vitro was normal. Furthermore, the endogenous rhythm of circadian gene expression, monitored in vitro by luciferase imaging of organotypical SCN slices removed from mice with disintegrated behavioral rhythms, was also normal. We concluded that abnormal behavioral and molecular circadian rhythms observed in R6/2 mice in vivo arise from dysfunction of brain circuitry afferent to the SCN, rather than from a primary deficiency within the pacemaker itself. Because circadian sleep disruption is deleterious to cognitive function, and cognitive decline is pronounced in R6/2 mice, we tested whether circadian and cognitive disturbances could be reversed by using a sedative drug to impose a daily cycle of sleep in R6/2 mice. Daily treatment with Alprazolam reversed the dysregulated expression of Per2 and also Prok2 , an output factor of the SCN that controls behavioral rhythms. It also markedly improved cognitive performance of R6/2 mice in a two-choice visual discrimination task. Together, our data show for the first time that treatments aimed at restoring circadian rhythms may not only slow the cognitive decline that is such a devastating feature of HD but may also improve other circadian gene-regulated functions that are impaired in this disease.
    Materialart: Online-Ressource
    ISSN: 0270-6474 , 1529-2401
    Sprache: Englisch
    Verlag: Society for Neuroscience
    Publikationsdatum: 2007
    ZDB Id: 1475274-8
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 30, No. 30 ( 2010-07-28), p. 10199-10204
    Kurzfassung: Behavioral circadian rhythms disintegrate progressively in the R6/2 mouse model of Huntington's disease (HD), recapitulating the sleep–wake disturbance seen in HD patients. Here we show that disturbances in circadian pacemaking are not restricted to the brain, but also encompass peripheral metabolic pathways in R6/2 mice. Notably, circadian rhythms of clock-driven genes that are key metabolic outputs in the liver are abolished in vivo . This deficiency is accompanied by arrhythmic expression of the clock genes Cry1 and Dbp , and a phase-advanced Per2 cycle. Compromised circadian metabolic cycles are not, however, a consequence of deficient pacemaking intrinsic to the liver, because when cultured in vitro , R6/2 liver slices exhibit self-sustained circadian bioluminescence rhythms. We therefore propose that compromised metabolic cycles arise from an internal desynchronization secondary to altered feeding patterns and impaired circadian signaling from the central pacemaker of the suprachiasmatic nucleus (SCN). Importantly, the SCN-independent food-entrainable oscillator remains intact in R6/2 mice and, when invoked, can restore daily behavioral cycles and reverse some of the metabolic abnormalities seen in the liver. Disturbances of metabolism have long been thought to be an important feature of HD. Uncoupling liver metabolism from circadian drives will reduce metabolic efficiency and cause imbalances in metabolites known to be deleterious to brain function. Thus, even subtle imbalances in liver function may exacerbate symptoms of HD, where neurological function is already compromised.
    Materialart: Online-Ressource
    ISSN: 0270-6474 , 1529-2401
    Sprache: Englisch
    Verlag: Society for Neuroscience
    Publikationsdatum: 2010
    ZDB Id: 1475274-8
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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