Dynamic cellular processes such as differentiation are driven by changes in the abundances of transcription factors (TFs). However, despite years of studies, our knowledge about the protein copy ...number of TFs in the nucleus is limited. Here, by determining the absolute abundances of 103 TFs and co-factors during the course of human erythropoiesis, we provide a dynamic and quantitative scale for TFs in the nucleus. Furthermore, we establish the first gene regulatory network of cell fate commitment that integrates temporal protein stoichiometry data with mRNA measurements. The model revealed quantitative imbalances in TFs’ cross-antagonistic relationships that underlie lineage determination. Finally, we made the surprising discovery that, in the nucleus, co-repressors are dramatically more abundant than co-activators at the protein level, but not at the RNA level, with profound implications for understanding transcriptional regulation. These analyses provide a unique quantitative framework to understand transcriptional regulation of cell differentiation in a dynamic context.
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•Absolute quantification of endogenous transcription factors in human erythropoiesis•Co-repressors are in large excess while co-activators are limiting in the nucleus•Quantitative model of erythropoiesis integrating changes in protein and mRNA amounts•A website for human erythropoiesis transcription factors proteins and transcripts
Protein stoichiometry in the nucleus is mostly unknown. Gillespie et al. use targeted mass spectrometry to quantify over a hundred transcription factors during human erythropoiesis. The data reveal co-repressors are on average 100 times more abundant than co-activators. Furthermore, a quantitative model of erythropoiesis integrating mRNA and protein abundances is generated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Introduction This article reviews the work done in the Alzheimer's Disease Neuroimaging Initiative positron emission tomography (ADNI PET) core over the past 5 years, largely concerning ...techniques, methods, and results related to amyloid imaging in ADNI. Methods The PET Core has used 18 Fflorbetapir routinely on ADNI participants, with over 1600 scans available for download. Four different laboratories are involved in data analysis, and have examined factors such as longitudinal florbetapir analysis, use of 18 Ffluorodeoxyglucose (FDG)-PET in clinical trials, and relationships between different biomarkers and cognition. Results Converging evidence from the PET Core has indicated that cross-sectional and longitudinal florbetapir analyses require different reference regions. Studies have also examined the relationship between florbetapir data obtained immediately after injection, which reflects perfusion, and FDG-PET results. Finally, standardization has included the translation of florbetapir PET data to a centiloid scale. Conclusion The PET Core has demonstrated a variety of methods for the standardization of biomarkers such as florbetapir PET in a multicenter setting.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The western corn rootworm (WCR), Diabrotica virgifera virgifera LeConte, is an economically important pest of field corn (Zea mays L.) across the United States (U.S.) Corn Belt. Repeated use of ...transgenic hybrids expressing Bacillus thuringiensis (Bt) proteins has selected for field-evolved resistance to all current rootworm-active Bt proteins. The newest product available for WCR management is SmartStax® PRO, a rootworm-active pyramid containing Cry3Bb1, Cry34/35Ab1 now reclassified as Gpp34Ab1/Tpp35Ab1 and a new mode of action, DvSnf7 dsRNA. Understanding the fitness of adult WCR after dietary exposure to SmartStax® PRO will identify potential impacts on WCR population dynamics and inform efforts to optimize resistance management strategies. Therefore, the objective of the present study was to characterize the effect of SmartStax® PRO dietary exposure on WCR life history traits. Adult WCR were collected during 2018 and 2019 from emergence tents placed over replicated field plots of SmartStax® PRO or non-rootworm Bt corn at a site with a history of rootworm-Bt trait use and suspected resistance to Cry3Bb1 and Cry34/35Ab1. Adult survival was reduced by 97.1-99.7% in SmartStax® PRO plots relative to the non-rootworm Bt corn plots during the study. Individual male/female pairs were fed different diets of ear tissue to simulate lifetime or adult exposure. Life history parameters measured included adult longevity, adult head capsule width, lifetime female egg production, and egg viability. Results indicate that lifetime or adult exposure to SmartStax® PRO significantly reduced adult longevity and lifetime egg production. Larval exposure to SmartStax® PRO significantly reduced WCR adult size. Results from this study collectively suggest that SmartStax® PRO may negatively impact WCR life history traits, which may lead to reduced population growth when deployed in an area with WCR resistance to Bt traits.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Treatment of many pathologies of the brain could be improved markedly by the development of noninvasive therapeutic approaches that elicit robust, endothelial cell-selective gene expression in ...specific brain regions that are targeted under MR image guidance. While focused ultrasound (FUS) in conjunction with gas-filled microbubbles (MBs) has emerged as a noninvasive modality for MR image-guided gene delivery to the brain, it has been used exclusively to transiently disrupt the blood–brain barrier (BBB), which may induce a sterile inflammation response. Here, we introduce an MR image-guided FUS method that elicits endothelialselective transfection of the cerebral vasculature (i.e., “sonoselective” transfection), without opening the BBB. We first determined that activating circulating, cationic plasmid-bearing MBs with pulsed low-pressure (0.1 MPa) 1.1-MHz FUS facilitates sonoselective gene delivery to the endothelium without MRI-detectable disruption of the BBB. The degree of endothelial selectivity varied inversely with the FUS pressure, with higher pressures (i.e., 0.3-MPa and 0.4-MPa FUS) consistently inducing BBB opening and extravascular transfection. Bulk RNA sequencing analyses revealed that the sonoselective low-pressure regimen does not up-regulate inflammatory or immune responses. Single-cell RNA sequencing indicated that the transcriptome of sonoselectively transfected brain endothelium was unaffected by the treatment. The approach developed here permits targeted gene delivery to blood vessels and could be used to promote angiogenesis, release endothelial cellsecreted factors to stimulate nerve regrowth, or recruit neural stem cells.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Abstract Background Few data exist on prevalence, morbidity, and mortality of pediatric heart failure hospitalizations. We tested the hypotheses that pediatric heart failure–related hospitalizations ...increased over time but that mortality decreased. Factors associated with mortality and length of stay were also assessed. Methods and Results A retrospective analysis of the Healthcare Cost and Utilization Project Kids' Inpatient Database was performed for pediatric (age ≤18 years) heart failure–related hospitalizations for the years 1997, 2000, 2003, and 2006. Hospitalizations did not significantly increase over time, ranging from 11,153 (95% confidence interval CI 8,898–13,409) in 2003 to 13,892 (95% CI 11,528–16,256) in 2006. Hospital length of stay increased from 1997 (mean 13.8 days, 95% CI 12.5–15.2) to 2006 (mean 19.4 days, 95% CI 18.2 to 20.6). Hospital mortality was 7.3% (95% CI 6.9–8.0) and did not vary significantly between years; however, risk-adjusted mortality was less in 2006 (odds ratio 0.70, 95% CI 0.61 to 0.80). The greatest risk of mortality occurred with extracorporeal membrane oxygenation, acute renal failure, and sepsis. Conclusions Heart failure–related hospitalizations occur in 11,000–14,000 children annually in the United States, with an overall mortality of 7%. Many comorbid conditions influenced hospital mortality.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
BACKGROUND—The incidence and impact of clinical stroke and silent radiographic cerebral infarction complicating open surgical aortic valve replacement (AVR) are poorly characterized.
METHODS AND ...RESULTS—We performed a prospective cohort study of subjects ≥65 years of age who were undergoing AVR for calcific aortic stenosis. Subjects were evaluated by neurologists preoperatively and postoperatively and underwent postoperative magnetic resonance imaging. Over a 4-year period, 196 subjects were enrolled at 2 sites (mean age, 75.8±6.2 years; 36% women; 6% nonwhite). Clinical strokes were detected in 17%, transient ischemic attack in 2%, and in-hospital mortality was 5%. The frequency of stroke in the Society for Thoracic Surgery database in this cohort was 7%. Most strokes were mild; the median National Institutes of Health Stroke Scale was 3 (interquartile range, 1–9). Clinical stroke was associated with increased length of stay (median, 12 versus 10 days; P=0.02). Moderate or severe stroke (National Institutes of Health Stroke Scale ≥10) occurred in 8 (4%) and was strongly associated with in-hospital mortality (38% versus 4%; P=0.005). Of the 109 stroke-free subjects with postoperative magnetic resonance imaging, silent infarct was identified in 59 (54%). Silent infarct was not associated with in-hospital mortality or increased length of stay.
CONCLUSIONS—Clinical stroke after AVR was more common than reported previously, more than double for this same cohort in the Society for Thoracic Surgery database, and silent cerebral infarctions were detected in more than half of the patients undergoing AVR. Clinical stroke complicating AVR is associated with increased length of stay and mortality.
Despite challenges due to the COVID-19 pandemic, reports from regional and national meetings of the Expanded Food and Nutrition Education program (EFNEP) have provided anecdotal evidence that the ...program has persevered, pivoted, and continued to positively impact the lives of some of the nation's most vulnerable populations. However, there have been necessary changes to program delivery, inevitable changes in the lives of participants, and changes in the food environment that may have impacted program outcomes. This study compares national EFNEP data (demographics, behavior change data, and 24 h dietary recall data) of participants from two federal fiscal years, before the COVID-19 pandemic and during the pandemic. Linear mixed model analysis of variance and covariance were used to assess the effects of year on program outcomes. Results of this study provide quantitative evidence of the resiliency of EFNEP to facilitate positive behavior changes related to diet quality, physical activity, food safety, food resource management, and food security. Amidst changes in the food environment during the COVID-19 pandemic, these results emphasize the importance and value of federal nutrition education programs in any food environment.
Left ventricular noncompaction (LVNC) is a reportedly uncommon genetic disorder of endocardial morphogenesis with a reportedly high mortality rate. The purpose of this study was to identify the ...clinical characteristics of children with LVNC.
We retrospectively reviewed 36 children with LVNC evaluated at Texas Children's Hospital (TCH) from January 1997 to December 2002. Five children had associated cardiac lesions. There were 16 girls and 20 boys. The median age at presentation was 90 days (range, 1 day to 17 years). The median duration of follow-up was 3.2 years (range, 0.5 to 12 years). Twenty-seven patients (75%) had ECG abnormalities, most commonly biventricular hypertrophy (10 patients, 28%). Both ventricles were involved in 8 patients (22%) and only the left ventricle in 28 patients (78%). Left ventricular systolic function was depressed in 30 patients (83%), with a median ejection fraction of 30% (range, 15% to 66%) at diagnosis. Nine patients presenting in the first year of life with depressed left ventricular contractility had a transient recovery of function; however, ejection fraction deteriorated later in life, at a median interval of 6.3years (range, 3 to 12 years). Two patients had an "undulating" phenotype from dilated to hypertrophic cardiomyopathy. Two patients (6%) were identified with an underlying G4.5 gene mutation. Five patients (14%) died during the study.
LVNC does not have an invariably fatal course when diagnosed in the neonatal period. A significant number of patients have transient recovery of function followed by later deterioration, which may account for many patients presenting as adults, some manifesting an "undulating" phenotype.
A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect ...on the balance between health and disease
. Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units
), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches
to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry
. These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Climate warming during the late Permian is associated with the most severe mass extinction event of the Phanerozoic, and the expansion of hypoxic and anoxic conditions in shallow shelf settings. It ...has been hypothesised that wave aeration provided a ‘habitable zone’ in the shallowest environments that allowed the survival and rapid recovery of benthic invertebrates during the Early Triassic. We test this hypothesis by studying the rock and fossil records of the Aggtelek Karst, Hungary. Nearshore settings recorded in the Bódvaszilas Sandstone Formation and units A and D of the Szin Marl Formation are characterised by taxonomically homogenous fossil assemblages of low diversity and low evenness. Ecological and taxonomic recovery in this environmental setting was hampered by persistent environmental stress. This stress is attributed to increased runoff related to climate warming during the Early Triassic that resulted in large salinity fluctuations, increased sedimentation rates and eutrophication that led to seasonal hypoxia and an environment only favourable for opportunistic taxa. In contrast, shoal and mid-ramp settings further offshore are characterised by high diversity faunas with a greater functional complexity. Prior to the late Spathian Tirolites carniolicus Zone, the shelly fossils and trace fossils are limited to settings aerated by wave activity, which supports the habitable zone hypothesis. In the Tirolites carniolicus Zone, however, the oxygen minimum zone retreats offshore and the habitable deeper shelf settings are rapidly colonised by shallow water taxa, evidenced by the highest levels of diversity and bioturbation recorded in the study. Locally, full recovery of marine ecosystems is not recorded until the Illyrian, with the establishment of a sponge reef complex.
•Faunal assemblages in proximal settings are characterised by low diversity and evenness values.•No faunal change was recorded across the Griesbachian/Dienerian boundary•Spathian recovery signal is associated with increased facies heterogeneity.•Outer ramp setting is rapidly colonised by shallow water fauna in the late Spathian.•The most taxonomically and ecologically diverse assemblages are recorded in the late Spathian.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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