Human immunodeficiency virus (HIV) infection is associated with increased intestinal translocation of microbial products and enteropathy as well as alterations in gut bacterial communities. However, ...whether the enteric virome contributes to this infection and resulting immunodeficiency remains unknown. We characterized the enteric virome and bacterial microbiome in a cohort of Ugandan patients, including HIV-uninfected or HIV-infected subjects and those either treated with anti-retroviral therapy (ART) or untreated. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and this increase was independent of ART treatment. Additionally, the enteric bacterial microbiome of patients with lower CD4 T counts exhibited reduced phylogenetic diversity and richness with specific bacteria showing differential abundance, including increases in Enterobacteriaceae, which have been associated with inflammation. Thus, immunodeficiency in progressive HIV infection is associated with alterations in the enteric virome and bacterial microbiome, which may contribute to AIDS-associated enteropathy and disease progression.
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•In HIV-infected Ugandans, low CD4 T cells were linked to enteric adenovirus expansion•Low CD4 T cell numbers were also associated with alterations in the bacterial microbiome•These changes in the virome and bacterial microbiome were independent of ART treatment•These changes may contribute to AIDS-associated enteropathy and disease progression
Monaco et al. characterize the enteric virome and bacterial microbiome in an HIV-infected Ugandan patient cohort. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and bacterial microbiome alterations, including increases in Enterobacteriaceae, each of which may contribute to AIDS-associated enteropathy and disease progression.
ABSTRACT We report on NuSTAR and Swift observations of a soft state of the neutron star low-mass X-ray binary GS 1826-24, commonly known as the "clocked" burster. The transition to the soft state was ...recorded in 2014 June through an increase of the 2-20 keV source intensity measured by MAXI, simultaneous with a decrease of the 15-50 keV intensity measured by Swift/BAT. The episode lasted approximately two months, after which the source returned to its usual hard state. We analyze the broadband spectrum measured by Swift/XRT and NuSTAR and estimate the accretion rate during the soft episode to be , within the range of previous observations. However, the best-fit spectral model, adopting the double Comptonization used previously, exhibits significantly softer components. We detect seven type-I X-ray bursts, all significantly weaker (and with shorter rise and decay times) than observed previously. The burst profiles and recurrence times vary significantly, ruling out the regular bursts that are typical for this source. One burst exhibited photospheric radius expansion and we estimate the source distance as kpc, where b parameterizes the possible anisotropy of the burst emission. The observed soft state may most likely be interpreted as a change in accretion geometry at about similar bolometric luminosity as in the hard state. The different burst behavior can therefore be attributed to this change in accretion flow geometry, but the fundamental cause and process for this effect remain unclear.
Intermediate-risk patients with aortic stenosis were randomly assigned to undergo either transcatheter or surgical aortic-valve replacement. At 5 years, there was no significant difference between ...the two groups in the incidence of death or disabling stroke. The incidence of aortic regurgitation was higher with transcatheter AVR.
The Department of Energy (DOE) supported Parallel Climate Model (PCM) makes use of the NCAR Community Climate Model (CCM3) and Land Surface Model (LSM) for the atmospheric and land surface ...components, respectively, the DOE Los Alamos National Laboratory Parallel Ocean Program (POP) for the ocean component, and the Naval Postgraduate School sea-ice model. The PCM executes on several distributed and shared memory computer systems. The coupling method is similar to that used in the NCAR Climate System Model (CSM) in that a flux coupler ties the components together, with interpolations between the different grids of the component models. Flux adjustments are not used in the PCM. The ocean component has 2/3° average horizontal grid spacing with 32 vertical levels and a free surface that allows calculation of sea level changes. Near the equator, the grid spacing is approximately 1/2° in latitude to better capture the ocean equatorial dynamics. The North Pole is rotated over northern North America thus producing resolution smaller than 2/3° in the North Atlantic where the sinking part of the world conveyor circulation largely takes place. Because this ocean model component does not have a computational point at the North Pole, the Arctic Ocean circulation systems are more realistic and similar to the observed. The elastic viscous plastic sea ice model has a grid spacing of 27km to represent small-scale features such as ice transport through the Canadian Archipelago and the East Greenland current region. Results from a 300year present-day coupled climate control simulation are presented, as well as for a transient 1% per year compound CO^sub 2^ increase experiment which shows a global warming of 1.27°C for a 10year average at the doubling point of CO^sub 2^ and 2.89°C at the quadrupling point. There is a gradual warming beyond the doubling and quadrupling points with CO^sub 2^ held constant. Globally averaged sea level rise at the time of CO^sub 2^ doubling is approximately 7cm and at the time of quadrupling it is 23cm. Some of the regional sea level changes are larger and reflect the adjustments in the temperature, salinity, internal ocean dynamics, surface heat flux, and wind stress on the ocean. A 0.5% per year CO^sub 2^ increase experiment also was performed showing a global warming of 1.5°C around the time of CO^sub 2^ doubling and a similar warming pattern to the 1% CO^sub 2^ per year increase experiment. El Niño and La Niña events in the tropical Pacific show approximately the observed frequency distribution and amplitude, which leads to near observed levels of variability on interannual time scales.PUBLICATION ABSTRACT
The heterogeneity of spontaneous preterm birth (SPTB) requires an interdisciplinary approach to determine potential predictive risk factors of early delivery. The aim of this study was to investigate ...maternal whole blood gene expression profiles associated with spontaneous preterm birth (SPTB, <37 weeks) in asymptomatic pregnant women. The study population was a matched subgroup of women (51 SPTBs, 114 term delivery controls) who participated in the All Our Babies community based cohort in Calgary (n = 1878). Maternal blood at 17-23 (sampling time point 1, T1) and 27-33 weeks of gestation (T2) were collected. Total RNA was extracted and microarray was performed on 326 samples (165 women). Univariate analyses determined significant clinical factors and differential gene expression associated with SPTB. Thirteen genes were validated using qRT-PCR. Three multivariate logistic models were constructed to identify gene expression at T1 (Model A), T2 (Model B), and gene expression fold change from T1 to T2 (Model C) associated with SPTB. All models were adjusted for clinical factors. Model C can predict SPTB with 65% sensitivity and 88% specificity in asymptomatic women after adjusting for history of abortion and anaemia (occurring before T2). Clinical data enhanced the sensitivity of the Models to predict SPTB. In conclusion, clinical factors and whole blood gene expression are associated with SPTB in asymptomatic women. An effective screening tool for SPTB during pregnancy would enable targeted preventive approaches and personalised antenatal care.
The role of cellular metabolism in regulating cell proliferation and differentiation remains poorly understood. For example, most mammalian cells cannot proliferate without exogenous glutamine ...supplementation even though glutamine is a non-essential amino acid. Here we show that mouse embryonic stem (ES) cells grown under conditions that maintain naive pluripotency are capable of proliferation in the absence of exogenous glutamine. Despite this, ES cells consume high levels of exogenous glutamine when the metabolite is available. In comparison to more differentiated cells, naive ES cells utilize both glucose and glutamine catabolism to maintain a high level of intracellular α-ketoglutarate (αKG). Consequently, naive ES cells exhibit an elevated αKG to succinate ratio that promotes histone/DNA demethylation and maintains pluripotency. Direct manipulation of the intracellular αKG/succinate ratio is sufficient to regulate multiple chromatin modifications, including H3K27me3 and ten-eleven translocation (Tet)-dependent DNA demethylation, which contribute to the regulation of pluripotency-associated gene expression. In vitro, supplementation with cell-permeable αKG directly supports ES-cell self-renewal while cell-permeable succinate promotes differentiation. This work reveals that intracellular αKG/succinate levels can contribute to the maintenance of cellular identity and have a mechanistic role in the transcriptional and epigenetic state of stem cells.
OBJECTIVE:Critically ill patients require high-intensity care and may be at especially high risk of iatrogenic injury because they are severely ill. We sought to study the incidence and nature of ...adverse events and serious errors in the critical care setting.
DESIGN:We conducted a prospective 1-year observational study. Incidents were collected with use of a multifaceted approach including direct continuous observation. Two physicians independently assessed incident type, severity, and preventability as well as systems-related and individual performance failures.
SETTING:Academic, tertiary-care urban hospital.
PATIENTS:Medical intensive care unit and coronary care unit patients.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:The primary outcomes of interest were the incidence and rates of adverse events and serious errors per 1000 patient-days. A total of 391 patients with 420 unit admissions were studied during 1490 patient-days. We found 120 adverse events in 79 patients (20.2%), including 66 (55%) nonpreventable and 54 (45%) preventable adverse events as well as 223 serious errors. The rates per 1000 patient-days for all adverse events, preventable adverse events, and serious errors were 80.5, 36.2, and 149.7, respectively. Among adverse events, 13% (16/120) were life-threatening or fatal; and among serious errors, 11% (24/223) were potentially life-threatening. Most serious medical errors occurred during the ordering or execution of treatments, especially medications (61%; 170/277). Performance level failures were most commonly slips and lapses (53%; 148/277), rather than rule-based or knowledge-based mistakes.
CONCLUSIONS:Adverse events and serious errors involving critically ill patients were common and often potentially life-threatening. Although many types of errors were identified, failure to carry out intended treatment correctly was the leading category.
Changes in memory performance are one of the hallmark symptoms of mild cognitive impairment and are affected by healthy aging as well. Pattern separation, which refers to the process of ...orthogonalizing overlapping inputs into distinct memory representations, may be a sensitive marker of these memory changes. Here, we describe a paradigm, the Behavioral Pattern Separation Task—Object Version (BPS-O task), which reveals age-related changes in pattern separation performance. Specifically, we report an age-related decline in pattern separation in healthy adults, ranging from ages 20 to 89. When we classify those individuals aged 60 and older into two groups, Aged Unimpaired (AU) and Aged Impaired (AI) based on their delayed word recall performance, we observe impairments in pattern separation performance in the Impaired group, but no overall impairment in recognition performance. In contrast, those individuals diagnosed with mild cognitive impairment demonstrate worse performance than age-matched controls in both pattern separation and recognition memory performance. Therefore, the BPS-O task provides a sensitive measure for observing changes in memory performance across the lifespan and may be useful for the early detection of memory impairments that may provide an early signal of later development to mild cognitive impairment.
► Behavioral pattern separation declines in human aging. ► MCI individuals exhibit impairments in both recognition memory and behavioral pattern separation. ► Aged Impaired adults demonstrate pattern separation deficits but normal recognition.
A robust network of transcription factors and an open chromatin landscape are hallmarks of the naive pluripotent state. Recently, the acetyllysine reader Brd4 has been implicated in stem cell ...maintenance, but the relative contribution of Brd4 to pluripotency remains unclear. Here, we show that Brd4 is dispensable for self-renewal and pluripotency of embryonic stem cells (ESCs). When maintained in their ground state, ESCs retain transcription factor binding and chromatin accessibility independent of Brd4 function or expression. In metastable ESCs, Brd4 independence can be achieved by increased expression of pluripotency transcription factors, including STAT3, Nanog or Klf4, so long as the DNA methylcytosine oxidases Tet1 and Tet2 are present. These data reveal that Brd4 is not essential for ESC self-renewal. Rather, the levels of pluripotency transcription factor abundance and Tet1/2 function determine the extent to which bromodomain recognition of protein acetylation contributes to the maintenance of gene expression and cell identity.
Purpose: We reported previously that ≥5 circulating tumor cells (CTC) in 7.5 mL blood at baseline and at first follow-up in 177 patients
with metastatic breast cancer (MBC) were associated with poor ...clinical outcome. In this study, additional follow-up data and
CTC levels at subsequent follow-up visits were evaluated.
Experimental Design: CTCs were enumerated in 177 MBC patients before the initiation of a new course of therapy (baseline) and 3 to 5, 6 to 8,
9 to 14, and 15 to 20 weeks after the initiation of therapy. Progression-free survival (PFS) and overall survival (OS) times
were calculated from the dates of each follow-up blood draw. Kaplan-Meier plots and survival analyses were done using a threshold
of ≥5 CTCs/7.5 mL at each blood draw.
Results: Median PFS times for patients with <5 CTC from each of the five blood draw time points were 7.0, 6.1, 5.6, 7.0, and 6.0 months,
respectively. For patients with ≥5 CTC, median PFS from these same time points was significantly shorter: 2.7, 1.3, 1.4, 3.0,
and 3.6 months, respectively. Median OS for patients with <5 CTC from the five blood draw time points was all >18.5 months.
For patients with ≥5 CTC, median OS from these same time points was significantly shorter: 10.9, 6.3, 6.3, 6.6, and 6.7 months,
respectively. Median PFS and OS times at baseline and up to 9 to 14 weeks after the initiation of therapy were statistically
significantly different.
Conclusions: Detection of elevated CTCs at any time during therapy is an accurate indication of subsequent rapid disease progression and
mortality for MBC patients.
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