35 research outputs found
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Comparisons of the M1 genome segments and encoded μ2 proteins of different reovirus isolates
BACKGROUND: The reovirus M1 genome segment encodes the μ2 protein, a structurally minor component of the viral core, which has been identified as a transcriptase cofactor, nucleoside and RNA triphosphatase, and microtubule-binding protein. The μ2 protein is the most poorly understood of the reovirus structural proteins. Genome segment sequences have been reported for 9 of the 10 genome segments for the 3 prototypic reoviruses type 1 Lang (T1L), type 2 Jones (T2J), and type 3 Dearing (T3D), but the M1 genome segment sequences for only T1L and T3D have been previously reported. For this study, we determined the M1 nucleotide and deduced μ2 amino acid sequences for T2J, nine other reovirus field isolates, and various T3D plaque-isolated clones from different laboratories. RESULTS: Determination of the T2J M1 sequence completes the analysis of all ten genome segments of that prototype. The T2J M1 sequence contained a 1 base pair deletion in the 3' non-translated region, compared to the T1L and T3D M1 sequences. The T2J M1 gene showed ~80% nucleotide homology, and the encoded μ2 protein showed ~71% amino acid identity, with the T1L and T3D M1 and μ2 sequences, respectively, making the T2J M1 gene and μ2 proteins amongst the most divergent of all reovirus genes and proteins. Comparisons of these newly determined M1 and μ2 sequences with newly determined M1 and μ2 sequences from nine additional field isolates and a variety of laboratory T3D clones identified conserved features and/or regions that provide clues about μ2 structure and function. CONCLUSIONS: The findings suggest a model for the domain organization of μ2 and provide further evidence for a role of μ2 in viral RNA synthesis. The new sequences were also used to explore the basis for M1/μ2-determined differences in the morphology of viral factories in infected cells. The findings confirm the key role of Ser/Pro208 as a prevalent determinant of differences in factory morphology among reovirus isolates and trace the divergence of this residue and its associated phenotype among the different laboratory-specific clones of type 3 Dearing
Alaska Volcano Observatory Alert and Forecasting Timeliness: 1989–2017
The Alaska Volcano Observatory (AVO) monitors volcanoes in Alaska and issues notifications and warnings of volcanic unrest and eruption. We evaluate the timeliness and accuracy of eruption forecasts for 53 eruptions at 20 volcanoes, beginning with Mount Redoubt's 1989–1990 eruption. Successful forecasts are defined as those where AVO issued a formal warning before eruption onset. These warning notifications are now part of AVO's Aviation Color Code and Volcanic Alert Level. This analysis considers only the start of an eruption, although many eruptions have multiple phases of activity. For the 21 eruptions at volcanoes with functioning local seismic networks, AVO has high forecasting success at volcanoes with: >15 years repose intervals and magmatic eruptions (4 out of 4, 100%); or larger eruptions (Volcanic Explosivity Index (VEI) 3 or greater; 6 out of 10, 60%). Therefore, AVO successfully forecast all four monitored, longer-repose period, VEI 3+ eruptions: Redoubt 1989–1990 and 2009, Spurr 1992, and Augustine 2005–2006. For volcanoes with functioning seismic monitoring networks, success rates are lower for: volcanoes with shorter repose periods (3 out of 16, 19%); more mafic compositions (3 out of 18, 17%); or smaller eruption size (VEI 2 or less, 1 out of 11, 9%). These eruptions (Okmok, Pavlof, Veniaminof, and Shishaldin) often lack detectable precursory signals. For 32 eruptions at volcanoes without functioning local seismic networks, the forecasting success rate is much lower (2, 6%; Kasatochi 2008 and Shishaldin 2014). For remote volcanoes where the main hazard is to aviation, rapid detection is a goal in the absence of in situ monitoring. Eruption detection has improved in recent years, shown by a decrease in the time between eruption onset and notification. Even limited seismic monitoring can detect precursory activity at volcanoes with certain characteristics (intermediate composition, longer repose times, larger eruptions), but difficulty persists in detecting subtle precursory activity at frequently active volcanoes with more mafic compositions. This suggests that volcano-specific characteristics should be considered when designing monitoring programs and evaluating forecasting success. More proximally-located sensors and data types are likely needed to forecast eruptive activity at frequently-active, more mafic volcanoes that generally produce smaller eruptions
Hemoglobin and cerebral hypoxic vasodilation in humans:Evidence for nitric oxide-dependent and S-nitrosothiol mediated signal transduction
Cerebral hypoxic vasodilation is poorly understood in humans, which undermines the development of therapeutics to optimize cerebral oxygen delivery. Across four investigations (total n = 195) we investigated the role of nitric oxide (NO) and hemoglobin-based S-nitrosothiol (RSNO) and nitrite ((Formula presented.)) signaling in the regulation of cerebral hypoxic vasodilation. We conducted hemodilution (n = 10) and NO synthase inhibition experiments (n = 11) as well as hemoglobin oxygen desaturation protocols, wherein we measured cerebral blood flow (CBF), intra-arterial blood pressure, and in subsets of participants trans-cerebral release/uptake of RSNO and (Formula presented.). Higher CBF during hypoxia was associated with greater trans-cerebral RSNO release but not (Formula presented.), while NO synthase inhibition reduced cerebral hypoxic vasodilation. Hemodilution increased the magnitude of cerebral hypoxic vasodilation following acute hemodilution, while in 134 participants tested under normal conditions, hypoxic cerebral vasodilation was inversely correlated to arterial hemoglobin concentration. These studies were replicated in a sample of polycythemic high-altitude native Andeans suffering from excessive erythrocytosis (n = 40), where cerebral hypoxic vasodilation was inversely correlated to hemoglobin concentration, and improved with hemodilution (n = 6). Collectively, our data indicate that cerebral hypoxic vasodilation is partially NO-dependent, associated with trans-cerebral RSNO release, and place hemoglobin-based NO signaling as a central mechanism of cerebral hypoxic vasodilation in humans.</p
Short-Term Forecasting and Detection of Explosions During the 2016–2017 Eruption of Bogoslof Volcano, Alaska
We describe a multidisciplinary approach to forecast, rapidly detect, and characterize explosive events during the 2016–2017 eruption of Bogoslof volcano, a back-arc shallow submarine volcano in Alaska’s Aleutian arc. The eruptive sequence began in December 2016 and included about 70 discrete explosive events. Because the volcano has no local monitoring stations, we used distant stations on the nearest volcanoes, Okmok (54 km) and Makushin (72 km), combined with regional infrasound sensors and lightning detection from the Worldwide Lightning Location Network (WWLLN). Pre-eruptive seismicity was detected for 12 events during the first half of the eruption; for all other events co-eruptive signals allowed for detection only. Monitoring of activity used a combination of scheduled checks combined with automated alarms. Alarms triggered on real-time data included real-time seismic amplitude measurement (RSAM); infrasound from several arrays, the closest being on Okmok; and lightning strokes detected from WWLLN within a 20-km radius of the volcano. During periods of unrest, a multidisciplinary response team of four people fulfilled specific roles to evaluate geophysical and remote-sensing data, run event-specific ash-cloud dispersion models, ensure interagency coordination, and develop and distribute of formalized warning products. Using this approach, for events that produced ash clouds ≥7.5 km above sea level, Alaska Volcano Observatory (AVO) called emergency response partners 15 min, and issued written notices 30 min, after event onset (mean times). Factors that affect timeliness of written warnings include event size and number of data streams available; bigger events and more data both decrease uncertainty and allow for faster warnings. In remote areas where airborne ash is the primary hazard, the approach used at Bogoslof is an effective strategy for hazard mitigation
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Characterizing Long COVID in Children and Adolescents
ImportanceMost research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment.ObjectiveTo identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC.Design, setting, and participantsMulticenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history.ExposureSARS-CoV-2 infection.Main outcomes and measuresPASC and 89 prolonged symptoms across 9 symptom domains.ResultsA total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents.Conclusions and relevanceThis study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges
Food Insecurity Prevalence Across Diverse Sites During COVID-19: A Year of Comprehensive Data
Key Findings NFACT includes 18 study sites in 15 states as well as a national poll, collectively representing a sample size of more than 26,000 people. Some sites have implemented multiple survey rounds, here we report results from 22 separate surveys conducted during the year since the COVID-19 pandemic began in March 2020. 18 out of 19 surveys in 14 sites with data for before and since the pandemic began found an increase in food insecurity since the start of the COVID-19 pandemic as compared to before the pandemic. In nearly all surveys (18/19) that measured food insecurity both before and during the pandemic, more Black, Indigenous, and People of Color (BIPOC) were classified as food insecure during the pandemic as compared to before it began. Prevalence of food insecurity for BIPOC respondents was higher than the overall population in the majority of surveys (19/20) sampling a general population. In almost all surveys (21/22), the prevalence of food insecurity for households with children was higher than the overall prevalence of food insecurity. Food insecurity prevalence was higher for households experiencing a negative job impact during the pandemic (i.e. job loss, furlough, reduction in hours) in nearly all surveys and study sites (21/22). Food insecurity prevalence in most sites was significantly higher before COVID-19 than estimates from that time period. Reporting a percent change between pre and during COVID-19 prevalence may provide additional information about the rate of change in food insecurity since the start of the pandemic, which absolute prevalence of food insecurity may not capture. Results highlight consistent trends in food insecurity outcomes since the start of the COVID-19 pandemic, across diverse study sites, methodological approaches, and time
Relationships of Cetacea (Artiodactyla) Among Mammals: Increased Taxon Sampling Alters Interpretations of Key Fossils and Character Evolution
BACKGROUND: Integration of diverse data (molecules, fossils) provides the most robust test of the phylogeny of cetaceans. Positioning key fossils is critical for reconstructing the character change from life on land to life in the water. METHODOLOGY/PRINCIPAL FINDINGS: We reexamine relationships of critical extinct taxa that impact our understanding of the origin of Cetacea. We do this in the context of the largest total evidence analysis of morphological and molecular information for Artiodactyla (661 phenotypic characters and 46,587 molecular characters, coded for 33 extant and 48 extinct taxa). We score morphological data for Carnivoramorpha, Creodonta, Lipotyphla, and the raoellid artiodactylan Indohyus and concentrate on determining which fossils are positioned along stem lineages to major artiodactylan crown clades. Shortest trees place Cetacea within Artiodactyla and close to Indohyus, with Mesonychia outside of Artiodactyla. The relationships of Mesonychia and Indohyus are highly unstable, however--in trees only two steps longer than minimum length, Mesonychia falls inside Artiodactyla and displaces Indohyus from a position close to Cetacea. Trees based only on data that fossilize continue to show the classic arrangement of relationships within Artiodactyla with Cetacea grouping outside the clade, a signal incongruent with the molecular data that dominate the total evidence result. CONCLUSIONS/SIGNIFICANCE: Integration of new fossil material of Indohyus impacts placement of another extinct clade Mesonychia, pushing it much farther down the tree. The phylogenetic position of Indohyus suggests that the cetacean stem lineage included herbivorous and carnivorous aquatic species. We also conclude that extinct members of Cetancodonta (whales+hippopotamids) shared a derived ability to hear underwater sounds, even though several cetancodontans lack a pachyostotic auditory bulla. We revise the taxonomy of living and extinct artiodactylans and propose explicit node and stem-based definitions for the ingroup
Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have
fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in
25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16
regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of
correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP,
while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in
Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium
(LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region.
Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant
enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the
refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa,
an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of
PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent
signals within the same regio