To evaluate factors associated with discontinuation of pulmonary vasodilator therapy in bronchopulmonary dysplasia-related pulmonary hypertension (BPD-PH).
Retrospective study of neonatal, ...echocardiographic, and cardiac catheterization data in 121 infants with BPD-PH discharged on pulmonary vasodilator therapy from 2009-2020 and followed into childhood.
After median 4.4 years, medications were discontinued in 58%. Those in whom medications were discontinued had fewer days of invasive support, less severe BPD, lower incidence of PDA closure or cardiac catheterization, and higher incidence of fundoplication or tracheostomy decannulation (p < 0.05). On multivariable analysis, likelihood of medication discontinuation was lower with longer period of invasive respiratory support HR 0.95 (CI:0.91-0.99), p = 0.01 and worse RV dilation on pre-discharge echocardiogram HR 0.13 (CI:0.03-0.70), p = 0.017. In those with tracheostomy, likelihood of medication discontinuation was higher with decannulation HR 10.78 (CI:1.98-58.59), p < 0.001.
In BPD-PH, childhood discontinuation of pulmonary vasodilator therapy is associated with markers of disease severity.
Leukemias bearing fusions of the AF10/MLLT10 gene are associated with poor prognosis, and therapies targeting these fusion proteins (FPs) are lacking. To understand mechanisms underlying AF10 ...fusion-mediated leukemogenesis, we generated inducible mouse models of acute myeloid leukemia (AML) driven by the most common AF10 FPs, PICALM/CALM-AF10 and KMT2A/MLL-AF10, and performed comprehensive characterization of the disease using transcriptomic, epigenomic, proteomic, and functional genomic approaches. Our studies provide a detailed map of gene networks and protein interactors associated with key AF10 fusions involved in leukemia. Specifically, we report that AF10 fusions activate a cascade of JAK/STAT-mediated inflammatory signaling through direct recruitment of JAK1 kinase. Inhibition of the JAK/STAT signaling by genetic Jak1 deletion or through pharmacological JAK/STAT inhibition elicited potent antioncogenic effects in mouse and human models of AF10 fusion AML. Collectively, our study identifies JAK1 as a tractable therapeutic target in AF10-rearranged leukemias.
•We comprehensively characterized AF10 FPs, identifying downstream transcriptional networks and protein interactors.•We show that AF10 FPs recruit the JAK1 kinase, which is required for the activation of downstream targets and leukemogenesis.
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Brain-type natriuretic peptide (BNP) correlates with pulmonary hypertension as demonstrated by echocardiogram in congenital diaphragmatic hernia (CDH); however, its association with right ventricular ...(RV) function and mortality is unknown.
To characterize the relationships between echocardiogram-derived RV strain, BNP, and mortality in diaphragmatic hernia.
We performed a single-center retrospective cohort study of infants with CDH and at least one BNP-echocardiogram pair within a 24-hour period. RV global longitudinal strain (GLS) and free-wall strain (FWS) were measured on existing echocardiograms. Associations among strain, BNP, and mortality were tested using mixed-effect linear and logistic regression models. Survival analysis was stratified by BNP and strain abnormalities.
There were 220 infants with 460 BNP-echocardiogram pairs obtained preoperatively (
= 237), ≤1 week postoperatively (
= 35), and >1 week postoperatively ("recovery";
= 188). Strain improved after repair (
< 0.0001 for all periods). Higher BNP level was associated with worse strain in recovery but not before or immediately after operation (estimate 95% confidence interval for recovery: GLS, 1.03 0.50-1.57;
= 0.0003; FWS, 0.62 0.01-1.22;
= 0.047). BNP and strain abnormalities were associated with an extracorporeal-membrane oxygenation requirement. Higher BNP level in recovery was associated with greater mortality (odds ratio, 11.2 1.2-571.3;
= 0.02). Abnormal strain in recovery had high sensitivity for detection of mortality (100% for GLS; 100% for FWS) but had low specificity for detection of mortality (28% for GLS; 48% for FWS).
Persistent RV dysfunction after CDH repair may be detected by a high BNP level and abnormal RV strain.
While the fundamental importance of the white matter in supporting neuronal communication is well known, existing publications of primate brains do not feature a detailed description of its complex ...anatomy. The main barrier to achieving this is that existing primate neuroimaging data have insufficient spatial resolution to resolve white matter pathways fully. Here we present a resource that allows detailed descriptions of white matter structures and trajectories of fiber pathways in the marmoset brain. The resource includes: (1) the highest-resolution diffusion-weighted MRI data available to date, which reveal white matter features not previously described; (2) a comprehensive three-dimensional white matter atlas depicting fiber pathways that were either omitted or misidentified in previous atlases; and (3) comprehensive fiber pathway maps of cortical connections combining diffusion-weighted MRI tractography and neuronal tracing data. The resource, which can be downloaded from marmosetbrainmapping.org, will facilitate studies of brain connectivity and the development of tractography algorithms in the primate brain.
The purpose of this program is to address problems of peer aggression and victimization that are so prevalent in schools. A number of factors have been found to contribute to the development of ...aggression in children, such as parental influences, peer networks, and environmental factors. The Linking Everyone in Aggression Prevention in Schools (LEAPS) program was developed to address these problems, using empirically supported behavioral methods. Specifically, the program aims at preventing and reducing reactive and proactive aggressive responses in students. The target population consists of youth aged 11–14 in middle school, school personnel, and the parents of youth referred for individual treatment. The program's behavioral treatment strategies involve a school-wide intervention, group skill training, individual treatment, and parent behavior management training in preventing and reducing student aggressive behavior in school while promoting pro-social interaction in the targeted population.
Understanding the intrinsic mediators that render CD8
T cells dysfunctional in the tumor microenvironment is a requirement to develop more effective cancer immunotherapies. Here, we report that ...C/EBP homologous protein (Chop), a downstream sensor of severe endoplasmic reticulum (ER) stress, is a major negative regulator of the effector function of tumor-reactive CD8
T cells. Chop expression is increased in tumor-infiltrating CD8
T cells, which correlates with poor clinical outcome in ovarian cancer patients. Deletion of Chop in T cells improves spontaneous antitumor CD8
T cell immunity and boosts the efficacy of T cell-based immunotherapy. Mechanistically, Chop in CD8
T cells is elevated primarily through the ER stress-associated kinase Perk and a subsequent induction of Atf4; and directly represses the expression of T-bet, a master regulator of effector T cell function. These findings demonstrate the primary role of Chop in tumor-induced CD8
T cell dysfunction and the therapeutic potential of blocking Chop or ER stress to unleash T cell-mediated antitumor immunity.
Globalized infectious diseases are causing species declines worldwide, but their source often remains elusive. We used whole-genome sequencing to solve the spatiotemporal origins of the most ...devastating panzootic to date, caused by the fungus
, a proximate driver of global amphibian declines. We traced the source of
to the Korean peninsula, where one lineage,
ASIA-1, exhibits the genetic hallmarks of an ancestral population that seeded the panzootic. We date the emergence of this pathogen to the early 20th century, coinciding with the global expansion of commercial trade in amphibians, and we show that intercontinental transmission is ongoing. Our findings point to East Asia as a geographic hotspot for
biodiversity and the original source of these lineages that now parasitize amphibians worldwide.
The 2017–2027 National Academies' Decadal Survey, Thriving on Our Changing Planet, recommended Surface Biology and Geology (SBG) as a “Designated Targeted Observable” (DO). The SBG DO is based on the ...need for capabilities to acquire global, high spatial resolution, visible to shortwave infrared (VSWIR; 380–2500 nm; ~30 m pixel resolution) hyperspectral (imaging spectroscopy) and multispectral midwave and thermal infrared (MWIR: 3–5 μm; TIR: 8–12 μm; ~60 m pixel resolution) measurements with sub-monthly temporal revisits over terrestrial, freshwater, and coastal marine habitats. To address the various mission design needs, an SBG Algorithms Working Group of multidisciplinary researchers has been formed to review and evaluate the algorithms applicable to the SBG DO across a wide range of Earth science disciplines, including terrestrial and aquatic ecology, atmospheric science, geology, and hydrology. Here, we summarize current state-of-the-practice VSWIR and TIR algorithms that use airborne or orbital spectral imaging observations to address the SBG DO priorities identified by the Decadal Survey: (i) terrestrial vegetation physiology, functional traits, and health; (ii) inland and coastal aquatic ecosystems physiology, functional traits, and health; (iii) snow and ice accumulation, melting, and albedo; (iv) active surface composition (eruptions, landslides, evolving landscapes, hazard risks); (v) effects of changing land use on surface energy, water, momentum, and carbon fluxes; and (vi) managing agriculture, natural habitats, water use/quality, and urban development. We review existing algorithms in the following categories: snow/ice, aquatic environments, geology, and terrestrial vegetation, and summarize the community-state-of-practice in each category. This effort synthesizes the findings of more than 130 scientists.
•The 2017 Decadal Survey recommended Surface Biology and Geology mission•Visible to shortwave infrared hyperspectral and multi-band thermal data•Global high resolution measurements at sub-monthly temporal resolution•Applications in snow/ice, aquatic environment, geology, and terrestrial vegetation•We review existing relevant algorithms and community-state-of-practice
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•Large-scale molecular phylogenetic synthesis of the third largest class of fungi.•Based on a cumulative supermatrix approach of >1100 species representing all orders.•Up to ca. 8kb ...from four nuclear and one mitochondrial genes were included per species.•Comprehensive revision of classification including 74 taxonomic conclusions.•A new module “Hypha” of the Mesquite software is introduced.
The Lecanoromycetes is the largest class of lichenized Fungi, and one of the most species-rich classes in the kingdom. Here we provide a multigene phylogenetic synthesis (using three ribosomal RNA-coding and two protein-coding genes) of the Lecanoromycetes based on 642 newly generated and 3329 publicly available sequences representing 1139 taxa, 317 genera, 66 families, 17 orders and five subclasses (four currently recognized: Acarosporomycetidae, Lecanoromycetidae, Ostropomycetidae, Umbilicariomycetidae; and one provisionarily recognized, ‘Candelariomycetidae’). Maximum likelihood phylogenetic analyses on four multigene datasets assembled using a cumulative supermatrix approach with a progressively higher number of species and missing data (5-gene, 5+4-gene, 5+4+3-gene and 5+4+3+2-gene datasets) show that the current classification includes non-monophyletic taxa at various ranks, which need to be recircumscribed and require revisionary treatments based on denser taxon sampling and more loci. Two newly circumscribed orders (Arctomiales and Hymeneliales in the Ostropomycetidae) and three families (Ramboldiaceae and Psilolechiaceae in the Lecanorales, and Strangosporaceae in the Lecanoromycetes inc. sed.) are introduced. The potential resurrection of the families Eigleraceae and Lopadiaceae is considered here to alleviate phylogenetic and classification disparities. An overview of the photobionts associated with the main fungal lineages in the Lecanoromycetes based on available published records is provided. A revised schematic classification at the family level in the phylogenetic context of widely accepted and newly revealed relationships across Lecanoromycetes is included. The cumulative addition of taxa with an increasing amount of missing data (i.e., a cumulative supermatrix approach, starting with taxa for which sequences were available for all five targeted genes and ending with the addition of taxa for which only two genes have been sequenced) revealed relatively stable relationships for many families and orders. However, the increasing number of taxa without the addition of more loci also resulted in an expected substantial loss of phylogenetic resolving power and support (especially for deep phylogenetic relationships), potentially including the misplacements of several taxa. Future phylogenetic analyses should include additional single copy protein-coding markers in order to improve the tree of the Lecanoromycetes. As part of this study, a new module (“Hypha”) of the freely available Mesquite software was developed to compare and display the internodal support values derived from this cumulative supermatrix approach.
Ways to prevent gestational diabetes mellitus (GDM) remain unproven. We compared the impact of three lifestyle interventions (healthy eating HE, physical activity PA, and both HE and PA HE+PA) on GDM ...risk in a pilot multicenter randomized trial.
Pregnant women at risk for GDM (BMI ≥29 kg/m2) from nine European countries were invited to undertake a 75-g oral glucose tolerance test before 20 weeks' gestation. Those without GDM were randomized to HE, PA, or HE+PA. Women received five face-to-face and four optional telephone coaching sessions, based on the principles of motivational interviewing. A gestational weight gain (GWG) <5 kg was targeted. Coaches received standardized training and an intervention toolkit. Primary outcome measures were GWG, fasting glucose, and insulin sensitivity (HOMA) at 35-37 weeks.
Among the 150 trial participants, 32% developed GDM by 35-37 weeks and 20% achieved GWG <5 kg. HE women had less GWG (-2.6 kg 95% CI -4.9, -0.2; P = 0.03) and lower fasting glucose (-0.3 mmol/L -0.4, -0.1; P = 0.01) than those in the PA group at 24-28 weeks. HOMA was comparable. No significant differences between HE+PA and the other groups were observed.
An antenatal HE intervention is associated with less GWG and lower fasting glucose compared with PA alone. These findings require a larger trial for confirmation but support the use of early HE interventions in obese pregnant women.
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