ETV6 germline mutations cause HDAC3/NCOR2 mislocalization and upregulation of interferon response genes

ETV6 is an ETS family transcription factor that plays a key role in hematopoiesis and megakaryocyte development. Our group and others have identified germline mutations in ETV6 resulting in autosomal dominant thrombocytopenia and predisposition to malignancy; however, molecular mechanisms defining the role of ETV6 in megakaryocyte development have not been well established. Using a combination of molecular, biochemical, and sequencing approaches in patient-derived PBMCs, we demonstrate abnormal cytoplasmic localization of ETV6 and the HDAC3/NCOR2 repressor complex that led to overexpression of HDAC3-regulated interferon response genes. This transcriptional dysregulation was also reflected in patient-derived platelet transcripts and drove aberrant proplatelet formation in megakaryocytes. Our results suggest that aberrant transcription may predispose patients with ETV6 mutations to bone marrow inflammation, dysplasia, and megakaryocyte dysfunction

Report on the 2013: Rapid assessment survey of marine species at New England Bays and Harbors

Introduced species (i.e., non-native species that have become established in\ud a new location) have increasingly been recognized as a concern as they have\ud become more prevalent in marine and terrestrial environments (Mooney and\ud Cleland 2001; Simberloff et al. 2005). The ability of introduced species to alter\ud population, community, and ecosystem structure and function, as well as\ud cause significant economic damage is well documented (Carlton 1989, 1996b,\ud 2000; Cohen and Carlton 1995; Cohen et al. 1995; Elton 1958; Meinesz et al.\ud 1993; Occhipinti-Ambrogi and Sheppard 2007; Pimentel et al. 2005; Thresher\ud 2000). The annual economic costs incurred from managing the approximately\ud 50,000 introduced species in the United States alone are estimated to be over\ud $120 billion (Pimentel et al. 2005).\ud Having a monitoring network in place to track new introductions and\ud distributional changes of introduced species is critical for effective\ud management, as these efforts may be more successful when species are\ud detected before they have the chance to become established. A rapid\ud assessment survey is one such method for early detection of introduced\ud species. With rapid assessment surveys, a team of taxonomic experts\ud record and monitor marine species–providing a baseline inventory of\ud native, introduced, and cryptogenic (i.e., unknown origin) species (as\ud defined by Carlton 1996a)–and document range expansions of previously\ud identified species.\ud Since 2000, five rapid assessment surveys have been conducted in New\ud England. These surveys focus on recording species at marinas, which often\ud are in close proximity to transportation vectors (i.e., recreational boats).\ud Species are collected from floating docks and piers because these structures\ud are accessible regardless of the tidal cycle. Another reason for sampling floating\ud docks and other floating structures is that marine introduced species are often\ud found to be more prevalent on artificial surfaces than natural surfaces (Glasby\ud and Connell 2001; Paulay et al. 2002). The primary objectives of these surveys\ud are to: (1) identify native, introduced, and cryptogenic marine species,\ud (2) expand on data collected in past surveys, (3) assess the introduction status\ud and range extensions of documented introduced species, and (4) detect new\ud introductions. This report presents the introduced, cryptogenic, and native\ud species recorded during the 2013 survey.CZM through NOAA NA13NOS4190040MIT Sea Grant through NOAA NA10OAR4170086

Особенности терапии атипичного герпеса и ассоциированного с ним рецидивирующего вульвовагинального кандидоза

КАНДИДОЗ ВУЛЬВОВАГИНАЛЬНЫЙ /ЛЕК ТЕРВЛАГАЛИЩА БОЛЕЗНИ /ЛЕК ТЕРВУЛЬВЫ БОЛЕЗНИ /ЛЕК ТЕРЖЕНСКИЕ БОЛЕЗНИ /ЛЕК ТЕРПРОТИВОГРИБКОВЫЕ СРЕДСТВАПРОТИВОВИРУСНЫЕ СРЕДСТВАГЕРПЕСВИРУСНЫЕ ИНФЕКЦИИРЕЦИДИВГЕРПЕСВИРУС 1 ЧЕЛОВЕКАГЕРПЕСВИРУС 2 ЧЕЛОВЕК

Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA

Primary pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of surfactant in the lungs that is presumed to be mediated by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling based on studies in genetically modified mice. The effects of GM-CSF are mediated by heterologous receptors composed of GM-CSF binding (GM-CSF-Rα) and nonbinding affinity-enhancing (GM-CSF-Rβ) subunits. We describe PAP, failure to thrive, and increased GM-CSF levels in two sisters aged 6 and 8 yr with abnormalities of both GM-CSF-Rα–encoding alleles (CSF2RA). One was a 1.6-Mb deletion in the pseudoautosomal region of one maternal X chromosome encompassing CSF2RA. The other, a point mutation in the paternal X chromosome allele encoding a G174R substitution, altered an N-linked glycosylation site within the cytokine binding domain and glycosylation of GM-CSF-Rα, severely reducing GM-CSF binding, receptor signaling, and GM-CSF–dependent functions in primary myeloid cells. Transfection of cloned cDNAs faithfully reproduced the signaling defect at physiological GM-CSF concentrations. Interestingly, at high GM-CSF concentrations similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow progression of disease in these children. These results establish that GM-CSF signaling is critical for surfactant homeostasis in humans and demonstrate that mutations in CSF2RA cause familial PAP

Clinical Research and Development of Tuberculosis Diagnostics: Moving From Silos to Synergy

The development, evaluation, and implementation of new and improved diagnostics have been identified as critical needs by human immunodeficiency virus (HIV) and tuberculosis researchers and clinicians alike. These needs exist in international and domestic settings and in adult and pediatric populations. Experts in tuberculosis and HIV care, researchers, healthcare providers, public health experts, and industry representatives, as well as representatives of pertinent US federal agencies (Centers for Disease Control and Prevention, Food and Drug Administration, National Institutes of Health, United States Agency for International Development) assembled at a workshop proposed by the Diagnostics Working Group of the Federal Tuberculosis Taskforce to review the state of tuberculosis diagnostics development in adult and pediatric populations

The incidence of Kawasaki disease using hospital admissions data for England 2006-2021

To describe the incidence of Kawasaki Disease (kDa) between 2006 and 2021 in England. We identified all cases in hospital episode statistics with an ICD-10 diagnostic code M303 (for kDa) between 1 April 2006 - 31 March 2021. We validated 83 diagnoses using hospital medical records and found >97% accuracy. We calculated incidence rate ratios (IRRs) using Poisson regression and assessed the influence of age, sex, ethnicity, and index of multiple deprivation (IMD). We used Office for National Statistics population estimates for England as the denominator. We identified a total of 5908 cases of kDa in all children under the age of 16 (mean age 3.8, SD = 3.2, 95% CI: 3.7-3.9). Incidence in children aged <5 years was 8.9 (95% CI: 8.6-9.2)/100 000 person-years; in children aged 5-9, 2.4 (95% CI: 2.3-2.6)/100 000 person-years; and in children aged 10-15, 0.6 (95% CI: 0.6-0.7). Male: female ratio was 1.5:1. Incidence was higher among non-White than White ethnicities (adjusted IRR 2.1 (2.0-2.2) for Asian, 3.0 (2.8-3.3) for Black and 4.5 (4.2-4.8) for other ethnicities). The incidence increased with socioeconomic deprivation; the adjusted IRR of the least deprived IMD quintile compared with the most deprived quintile was 0.81 (0.77-0.84). Incidence rates of kDa derived from hospital admission data in England were higher than in studies relying on clinician reporting. We confirm previous findings on the influence of sex, and ethnicity on kDa incidence and observe that there was a higher incidence of kDa within more deprived socioeconomic groups

The Impact of HIV, an Antiretroviral Programme and Tuberculosis on Mortality in South African Platinum Miners, 1992–2010

HIV and tuberculosis (TB) are the most common causes of death in South Africa. Antiretroviral therapy (ART) programmes should have had an impact on mortality rates. This study describes the impact of HIV, a Wellness (HIV/ART) programme and TB on population-wide trends in mortality and causes of death among South African platinum miners, from before the HIV epidemic into the ART era

Weight loss history as a predictor of weight loss: results from Phase I of the weight loss maintenance trial

Past studies have suggested that weight loss history is associated with subsequent weight loss. However, questions remain whether method and amount of weight lost in previous attempts impacts current weight loss efforts. This study utilized data from the Weight Loss Maintenance Trial to examine the association between weight loss history and weight loss outcomes in a diverse sample of high-risk individuals. Multivariate regression analysis was conducted to determine which specific aspects of weight loss history predict change in weight during a 6-month weight loss intervention. Greater weight loss was predicted by fewer previous weight loss attempts with assistance (p = 0.03), absence of previous dietary/herbal weight loss supplement use (p = 0.01), and greater maximum weight loss in previous attempts (p <0.001). Future interventions may benefit from assessment of weight loss history and tailoring of interventions based on past weight loss behaviors and outcomes

Reduced fire severity offers near-term buffer to climate-driven declines in conifer resilience across the western United States

Increasing fire severity and warmer, drier postfire conditions are making forests in the western United States (West) vulnerable to ecological transformation. Yet, the relative importance of and interactions between these drivers of forest change remain unresolved, particularly over upcoming decades. Here, we assess how the interactive impacts of changing climate and wildfire activity influenced conifer regeneration after 334 wildfires, using a dataset of postfire conifer regeneration from 10,230 field plots. Our findings highlight declining regeneration capacity across the West over the past four decades for the eight dominant conifer species studied. Postfire regeneration is sensitive to high-severity fire, which limits seed availability, and postfire climate, which influences seedling establishment. In the near-term, projected differences in recruitment probability between low- and high-severity fire scenarios were larger than projected climate change impacts for most species, suggesting that reductions in fire severity, and resultant impacts on seed availability, could partially offset expected climate-driven declines in postfire regeneration. Across 40 to 42% of the study area, we project postfire conifer regeneration to be likely following low-severity but not high-severity fire under future climate scenarios (2031 to 2050). However, increasingly warm, dry climate conditions are projected to eventually outweigh the influence of fire severity and seed availability. The percent of the study area considered unlikely to experience conifer regeneration, regardless of fire severity, increased from 5% in 1981 to 2000 to 26 to 31% by mid-century, highlighting a limited time window over which management actions that reduce fire severity may effectively support postfire conifer regeneration. © 2023 the Author(s)