There are significant challenges to the development of a pediatric norovirus vaccine, mainly due to the antigenic diversity among strains infecting young children. Characterizing human norovirus ...serotypes and understanding norovirus immunity in naïve children would provide key information for designing rational vaccine platforms. In this study, 26 Nicaraguan children experiencing their first norovirus acute gastroenteritis (AGE) episode during the first 18 months of life were investigated. We used a surrogate neutralization assay that measured antibodies blocking the binding of 13 different norovirus virus-like particles (VLPs) to histo-blood group antigens (HBGAs) in pre- and post-infection sera. To assess for asymptomatic norovirus infections, stools from asymptomatic children were collected monthly, screened for norovirus by RT-qPCR and genotyped by sequencing. Seroconversion of an HBGA-blocking antibody matched the infecting genotype in 25 (96%) of the 26 children. A subset of 13 (50%) and 4 (15%) of the 26 children experienced monotypic GII and GI seroconversion, respectively, strongly suggesting a type-specific response in naïve children, and 9 (35%) showed multitypic seroconversion. The most frequent pairing in multitypic seroconversion (8/12) were GII.4 Sydney and GII.12 noroviruses, both co-circulating at the time. Blocking antibody titers to these two genotypes did not correlate with each other, suggesting multiple exposure rather than cross-reactivity between genotypes. In addition, GII titers remained consistent for at least 19 months post-infection, demonstrating durable immunity. In conclusion, the first natural norovirus gastroenteritis episodes in these young children were dominated by a limited number of genotypes and induced responses of antibodies blocking binding of norovirus VLPs in a genotype-specific manner, suggesting that an effective pediatric norovirus vaccine likely needs to be multivalent and include globally dominant genotypes. The duration of protection from natural infections provides optimism for pediatric norovirus vaccines administered early in life.
Objectives:
The research question asked to what extent do self-rated performance scores of individual surgeons correspond to assessed procedural performance abilities and to peer ratings of ...procedural performance during a mass casualty (MASCAL) event?
Background:
Self-assessment using performance rating scales is ubiquitous in surgical education as a proxy for direct measurement of competence. The validity and reliability of self-ratings as competency measures are susceptible to cognitive biases such as Dunning-Kruger effects, which describe how individuals over/underestimate their own performance compared to assessments from independent sources. The ability of surgeons to accurately self-assess their procedural performance remains undetermined.
Methods:
A purposive sample of military surgeons (N = 13) who collectively cared for trauma patients during a MASCAL event participated in the study. Pre-event performance assessment scores for 32 trauma procedures were compared with post-event self and peer performance ratings using
F
tests (
P
< 0.05) and effect sizes (Cohen’s
d
).
Results:
There were no significant differences between peer ratings and performance assessment scores. There were significant differences between self-ratings and both peer ratings (
P
< 0.001) and performance assessment scores (
P
< 0.001). Effect sizes were very large for self to peer rating comparison (Cohen’s
d
= 2.34) and self to performance assessment comparison (Cohen’s
d
= 2.77).
Conclusions:
The outcomes demonstrate that self-ratings were significantly lower than the independently determined assessment scores for each surgeon, revealing a Dunning-Kruger effect for highly skilled individuals underestimating their abilities. These outcomes underscore the limitations of self-assessment for measuring competence.
Abstract
Building evolutionarily appropriate baseline models for natural populations is not only important for answering fundamental questions in population genetics—including quantifying the ...relative contributions of adaptive versus nonadaptive processes—but also essential for identifying candidate loci experiencing relatively rare and episodic forms of selection (e.g., positive or balancing selection). Here, a baseline model was developed for a human population of West African ancestry, the Yoruba, comprising processes constantly operating on the genome (i.e., purifying and background selection, population size changes, recombination rate heterogeneity, and gene conversion). Specifically, to perform joint inference of selective effects with demography, an approximate Bayesian approach was employed that utilizes the decay of background selection effects around functional elements, taking into account genomic architecture. This approach inferred a recent 6-fold population growth together with a distribution of fitness effects that is skewed towards effectively neutral mutations. Importantly, these results further suggest that, although strong and/or frequent recurrent positive selection is inconsistent with observed data, weak to moderate positive selection is consistent but unidentifiable if rare.
Hypoxia facilitates tumor invasion and metastasis by promoting neovascularization and co-option of tumor cells in the peritumoral vasculature, leading to dissemination of tumor cells into the ...circulation. However, until recently, animal models and imaging technology did not enable monitoring of the early events of tumor cell invasion and dissemination in living animals. We recently developed a zebrafish metastasis model to dissect the detailed events of hypoxia-induced tumor cell invasion and metastasis in association with angiogenesis at the single-cell level. In this model, fluorescent DiI-labeled human or mouse tumor cells are implanted into the perivitelline cavity of 48-h-old zebrafish embryos, which are subsequently placed in hypoxic water for 3 d. Tumor cell invasion, metastasis and pathological angiogenesis are detected under fluorescent microscopy in the living fish. The average experimental time for this model is 7 d. Our protocol offers a remarkable opportunity to study molecular mechanisms of hypoxia-induced cancer metastasis.
Yeast can be used to screen chemical libraries of human G protein-coupled receptors (GPCRs) faster and more cost-efficiently than mammalian cell line reporters.Yeast-based biosensors can screen and ...mate with microbial cell factories, based on relevant product titers, to accelerate the search for high-performance cell factories.Yeast mating correlates with surface-displayed protein–protein interaction strength and can be used to isolate strong binders, while machine learning-assisted protein engineering supports iterative high-quality libraries destined for experimental exploration by surface display on yeast.Engineered yeast systems can decode complex cellular communication, produce signaling modulators, and participate in human immune cell communication.The density of yeast surface-displayed signaling molecules can be GPCR-controlled to robustly target immune cell phenotypes via cell–cell communication.
Detailed molecular understanding of the human organism is essential to develop effective therapies. Saccharomyces cerevisiae has been used extensively for acquiring insights into important aspects of human health, such as studying genetics and cell–cell communication, elucidating protein–protein interaction (PPI) networks, and investigating human G protein-coupled receptor (hGPCR) signaling. We highlight recent advances and opportunities of yeast-based technologies for cost-efficient chemical library screening on hGPCRs, accelerated deciphering of PPI networks with mating-based screening and selection, and accurate cell–cell communication with human immune cells. Overall, yeast-based technologies constitute an important platform to support basic understanding and innovative applications towards improving human health.
Detailed molecular understanding of the human organism is essential to develop effective therapies. Saccharomyces cerevisiae has been used extensively for acquiring insights into important aspects of human health, such as studying genetics and cell–cell communication, elucidating protein–protein interaction (PPI) networks, and investigating human G protein-coupled receptor (hGPCR) signaling. We highlight recent advances and opportunities of yeast-based technologies for cost-efficient chemical library screening on hGPCRs, accelerated deciphering of PPI networks with mating-based screening and selection, and accurate cell–cell communication with human immune cells. Overall, yeast-based technologies constitute an important platform to support basic understanding and innovative applications towards improving human health.
HDAC7 associates with Runx2 and represses Runx2 transcriptional activity in a deacetylase‐independent manner. HDAC7 suppression accelerates osteoblast maturation. Thus, HDAC7 is a novel Runx2 ...co‐repressor that regulates osteoblast differentiation.
Introduction: Runx2 is a key regulator of gene expression in osteoblasts and can activate or repress transcription depending on interactions with various co‐factors. Based on previous observations that several histone deacetylases (HDACs) repress Runx2 activity and that HDAC inhibitors accelerate osteoblast differentiation in vitro, we hypothesized that additional HDACs may also affect Runx2 activity.
Materials and Methods: A panel of HDACs was screened for repressors of Runx2 activity. Immunofluorescence, co‐immunoprecipitation, GST‐pulldowns, and chromatin immunoprecipitations were used to characterize the interactions between Runx2 and HDAC7. Expression of osteoblast markers was examined in a C2C12 cell osteoblast differentiation model in which HDAC7 levels were reduced by RNAi.
Results: Runx2 activity was repressed by HDAC7 but not by HDAC9, HDRP, HDAC10, or HDAC11. HDAC7 and Runx2 were found co‐localized in nuclei and associated with Runx2‐responsive promoter elements in osseous cells. A carboxy‐terminal domain of Runx2 associated with multiple regions of HDAC7. Although direct interactions with Runx2 were confined to the carboxy terminus of HDAC7, this region was dispensable for repression. In contrast, the amino terminus of HDAC7 bound Runx2 indirectly and was necessary and sufficient for transcriptional repression. Treatment with HDAC inhibitors did not decrease inhibition by HDAC7, indicating that HDAC7 repressed Runx2 by deacetylation‐independent mechanism(s). Suppression of HDAC7 expression in C2C12 multipotent cells by RNAi accelerated their BMP2‐dependent osteoblast differentiation program. Consistent with this observation, BMP2 decreased nuclear localization of HDAC7.
Conclusions: These results establish HDAC7 as a regulator of Runx2's transcriptional activity and suggest that HDAC7 may be an important regulator of the timing and/ or rate of osteoblast maturation.
The distinct difference in disease phenotype of human papillomavirus-positive (HPV+) and -negative (HPV–) oropharyngeal squamous cell cancer (OPSCC) patients might also be apparent when assessing the ...effect of time to treatment initiation (TTI). We assessed the overall survival and progression-free survival (PFS) effect from increasing TTI for HPV+ and HPV– OPSCC patients.
We examined patients who received curative-intended therapy for OPSCC in eastern Denmark between 2000 and 2014. TTI was the number of days from diagnosis to the initiation of curative treatment. Overall survival and PFS were measured from the start of treatment and estimated with the Kaplan–Meier estimator. Hazard ratios and 95% confidence intervals were estimated with Cox proportional hazard regression.
At a median follow-up of 3.6 years (interquartile range 1.86–6.07 years), 1177 patients were included (59% HPV+). In the adjusted analysis for the HPV+ and HPV– patient population, TTI influenced overall survival and PFS, most evident in the HPV– group, where TTI >60 days statistically significantly influenced overall survival but not PFS (overall survival: hazard ratio 1.60; 95% confidence interval 1.04–2.45; PFS: hazard ratio 1.46; 95% confidence interval 0.96–2.22). For patients with a TTI >60 days in the HPV+ group, TTI affected overall survival and PFS similarly, with slightly lower hazard ratio estimates of 1.44 (95% confidence interval 0.83–2.51) and 1.15 (95% confidence interval 0.70–1.88), respectively.
For patients treated for a HPV+ or HPV– OPSCC, TTI affects outcome, with the strongest effect for overall survival among HPV– patients. Reducing TTI is an important tool to improve the prognosis.
•TTI affects outcome for both HPV+ and HPV– oropharyngeal cancer patients.•TTI has the strongest impact for OS among HPV– patients waiting > 60 days.•Reducing the diagnostic or treatment initiation delay is an essential tool to improve the prognosis for oropharyngeal cancer patients.
One of the central goals of evolutionary biology is to understand the genetic basis of adaptive evolution. The availability of nearly complete genome sequences from a variety of organisms has ...facilitated the collection of data on naturally occurring genetic variation on the scale of hundreds of loci to whole genomes. Such data have changed the focus of molecular population genetics from making inferences about adaptive evolution at single loci to identifying which loci, out of hundreds to thousands, have been recent targets of natural selection. A major challenge in this effort is distinguishing the effects of selection from those of the demographic history of populations. Here we review some current progress and remaining challenges in the field.
A wetland's ability to vertically accrete—capturing sediment and biological matter for soil accumulation—is key for maintaining elevation to counter soil subsidence and sea level rise. Wetland soil ...accretion is comprised of organic and inorganic components largely governed by net primary productivity and sedimentation. Sea level, land elevation, primary productivity, and sediment accretion are all changing across Louisiana's coastline, destabilizing much of its wetland ecosystems. In coastal Louisiana, analysis from 1984 to 2020 shows an estimated 1940.858 km2 of total loss at an average rate of 53.913 km2/year. Here we hypothesize that remote sensing timeseries data can provide suitable proxies for organic and inorganic accretionary components to estimate local accretion rates. The Landsat catalog offers decades of imagery applicable to tracking land extent changes across coastal Louisiana. This dataset's expansiveness allows it to be combined with the Coastwide Reference Monitoring System's point‐based accretion data. We exported normalized difference vegetation index (NDVI) and red‐band surface reflectance data for every available Landsat 4–8 scene across the coast using Google Earth Engine. Water pixels from the red‐band were transformed into estimates of total suspended solids to represent sediment deposition—the inorganic accretionary component. NDVI values over land pixels were used to estimate bioproductivity—representing accretion's organic component. We then developed a Random Forest regression model that predicts wetland accretion rates (R2 = 0.586, MAE = 0.333 cm/year). This model can inform wetland vulnerability assessments and loss predictions, and is to our knowledge the first remote sensing‐based model that directly estimates accretion rates in coastal wetlands.
Plain Language Summary
Soil accretion in coastal wetlands—whereby a wetland area builds its surface by capturing sediment and organic matter—helps counter land loss due to the compaction of soil and sea level rise. Coastal Louisiana has seen significant coastal wetland loss due widespread coastal engineering altering the processes that impact accretion. Remote sensing data can represent these processes, including organic matter production and sediment deposition, but they have not before been applied to directly model accretion rates. Here, we use Landsat timeseries data to model accretion based on derived estimates of suspended sediment availability and bioproductivity. These remote sensing inputs represent the primary inorganic and organic accretionary components, respectively. We additionally track changes in Louisiana's coastal wetland extent from 1984 to 2020 for comparison to our estimated accretion rates, estimating a total of 1940.858 km2 of total loss with a net change accounting for land gain of −1253.130 km2 at a rate of −34.809 km2/year. Our machine learning model results show significant accretion rate declines in coastal regions that experienced the greatest loss over the study period. Our remote sensing‐based model can inform future assessments of wetland vulnerability and loss predictions.
Key Points
In Louisiana from 1984 to 2020, we estimated 1940.9 km2 of wetland loss at a 53.9 km2/year rate (net change −1253.1 km2 and −34.8 km2/year)
We used machine learning to develop a remote sensing‐based model that directly estimates soil accretion rates in coastal wetlands
Accretion rates have significantly declined in the coastal basins that have lost the most wetland area
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