Saturn’s moon Enceladus has an ice-covered ocean; a plume of material erupts from cracks in the ice. The plume contains chemical signatures of water-rock interaction between the ocean and a rocky ...core. We used the Ion Neutral Mass Spectrometer onboard the Cassini spacecraft to detect molecular hydrogen in the plume. By using the instrument’s open-source mode, background processes of hydrogen production in the instrument were minimized and quantified, enabling the identification of a statistically significant signal of hydrogen native to Enceladus. We find that the most plausible source of this hydrogen is ongoing hydrothermal reactions of rock containing reduced minerals and organic materials. The relatively high hydrogen abundance in the plume signals thermodynamic disequilibrium that favors the formation of methane from CO₂ in Enceladus’ ocean.
In this paper we present status and plans for the 20- MeV R&D energy recovery linac (ERL), which is under construction at Collider Accelerator Department at BNL. The facility is based on high current ...(up to 0.5 A of average current) super-conducting 2.5 MeV RF gun,single-mode super-conducting 5-cell RF linac and about 20-m long return loop with very flexible lattice. The R&D ERL, which is planned for commissioning in early 2009, aims to address many outstanding questions relevant for high current, high brightness energy-recovery linacs.
Stimulus- or context-dependent routing of neural signals through parallel pathways can permit flexible processing of diverse inputs. For example, work in mouse shows that rod photoreceptor signals ...are routed through several retinal pathways, each specialized for different light levels. This light-level-dependent routing of rod signals has been invoked to explain several human perceptual results, but it has not been tested in primate retina. Here, we show, surprisingly, that rod signals traverse the primate retina almost exclusively through a single pathway - the dedicated rod bipolar pathway. Identical experiments in mouse and primate reveal substantial differences in how rod signals traverse the retina. These results require reevaluating human perceptual results in terms of flexible computation within this single pathway. This includes a prominent speeding of rod signals with light level - which we show is inherited directly from the rod photoreceptors themselves rather than from different pathways with distinct kinetics.
Disruption of epigenetic regulation is a hallmark of acute myeloid leukemia (AML), but epigenetic therapy is complicated by the complexity of the epigenome. Herein, we developed a long-term primary ...AML
platform to determine whether targeting different epigenetic layers with 5-azacytidine and LSD1 inhibitors would yield improved efficacy. This combination was most effective in
AML, where it extinguished leukemia stem cells and particularly induced genes with both LSD1-bound enhancers and cytosine-methylated promoters. Functional studies indicated that derepression of genes such as
contributes to drug efficacy. Mechanistically, combination therapy increased enhancer-promoter looping and chromatin-activating marks at the
locus. CRISPRi of the LSD1-bound enhancer in patient-derived
AML was associated with dampening of therapeutic
induction.
knockdown in human hematopoietic stem/progenitor cells induced loss of enhancer 5-hydroxymethylation and facilitated LSD1-mediated enhancer inactivation. Our data provide a basis for rational targeting of cooperating aberrant promoter and enhancer epigenetic marks driven by mutant epigenetic modifiers. SIGNIFICANCE: Somatic mutations of genes encoding epigenetic modifiers are a hallmark of AML and potentially disrupt many components of the epigenome. Our study targets two different epigenetic layers at promoters and enhancers that cooperate to aberrant gene silencing, downstream of the actions of a mutant epigenetic regulator.
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Despite significant advances in developing selective JAK2 inhibitors, JAK2 kinase inhibitor (TKI) therapy is ineffective in suppressing the disease. Reactivation of compensatory MEK-ERK and PI3K ...survival pathways sustained by inflammatory cytokine signaling causes treatment failure. Concomitant inhibition of MAPK pathway and JAK2 signaling showed improved in vivo efficacy compared to JAK2 inhibition alone but lacked clonal selectivity. We hypothesized that cytokine signaling in JAK2V617F induced MPNs increases the apoptotic threshold that causes TKI persistence or refractoriness. Here, we show that JAK2V617F and cytokine signaling converge to induce MAPK negative regulator, DUSP1. Enhanced DUSP1 expression blocks p38 mediated p53 stabilization. Deletion of Dusp1 increases p53 levels in the context of JAK2V617F signaling that causes synthetic lethality to Jak2V617F expressing cells. However, inhibition of Dusp1 by a small molecule inhibitor (BCI) failed to impart Jak2V617F clonal selectivity due to pErk1/2 rebound caused by off-target inhibition of Dusp6. Ectopic expression of Dusp6 and BCI treatment restored clonal selectively and eradicated the Jak2V617F cells. Our study shows that inflammatory cytokines and JAK2V617F signaling converge to induce DUSP1, which downregulates p53 and establishes a higher apoptotic threshold. These data suggest that selectively targeting DUSP1 may provide a curative response in JAK2V617F-driven MPN.
Helical cell shape is necessary for efficient stomach colonization by
, but the molecular mechanisms for generating helical shape remain unclear. The helical centerline pitch and radius of wild-type
...cells dictate surface curvatures of considerably higher positive and negative Gaussian curvatures than those present in straight- or curved-rod
. Quantitative 3D microscopy analysis of short pulses with either
-acetylmuramic acid or D-alanine metabolic probes showed that cell wall growth is enhanced at both sidewall curvature extremes. Immunofluorescence revealed MreB is most abundant at negative Gaussian curvature, while the bactofilin CcmA is most abundant at positive Gaussian curvature. Strains expressing CcmA variants with altered polymerization properties lose helical shape and associated positive Gaussian curvatures. We thus propose a model where CcmA and MreB promote PG synthesis at positive and negative Gaussian curvatures, respectively, and that this patterning is one mechanism necessary for maintaining helical shape.
Survival of naive T cells is dependent upon IL-7, which is present in vivo in limiting amounts with the result that naive T cells must compete for IL-7-mediated survival signals. It would seem ...imperative during T cell homeostasis that limiting IL-7 be shared by the greatest possible number of T cells. We now describe a novel regulatory mechanism that specifically suppresses IL7Rα transcription in response to IL-7 and other prosurvival cytokines (IL-2, IL-4, IL-6, and IL-15). Consequently, IL7R expression is reduced on T cells that have received cytokine-mediated survival signals so they do not compete with unsignaled T cells for remaining IL-7. Interestingly, cytokine-mediated suppression of IL7Rα transcription involves different molecular mechanisms in CD4
+ and CD8
+ T cells, as CD8
+ T cells utilize the transcriptional repressor GFI1 while CD4
+ T cells do not. We suggest that this homeostatic regulatory mechanism promotes survival of the maximum possible number of T cells for the amount of IL-7 available.
Wetlands provide unique habitat functions that benefit society by provisioning food, recreation, and ecosystem sustainability. Warfare affects the habitats of wetland-dependent reptiles, amphibians, ...and birds in both positive and negative ways, and opportunities exist to improve the management of wildlife habitat using a warfare ecology framework. Recent events in Ukraine highlight these relationships and provide stimulus to further consider the implications of current events for natural resources. In response, this commentary highlights both degradational and positive impacts of warfare on wetland fauna during the cyclical preparation, active conflict, and recovery phases. For example, the active conflict phase often initiates ecological disturbance regimes that couple large-scale landscape alteration with the release of chemicals and other materials into wetlands, leading to reduced reproductive potential and population declines in wetland-dependent species (e.g., amphibians, waterfowl) along with decreased overall wetland biodiversity and habitat quality. In contrast, wetland-dependent wildlife can benefit from (1) conservation activities occurring on military installations maintained to support training activities and (2) restoration efforts initiated after the cessation of combat. For example, many threatened and endangered reptiles and amphibians find refugia on military lands in the USA and internationally, and international protections for wetland resources (including the Ramsar Convention) have been established to promote their sustainability and wise use. Additional research is needed to improve the protection of valuable wetland resources by further enhancing ongoing conservation and planning efforts and improving strategies to mitigate the negative impacts of warfare on wetland dependent species throughout each phase of the warfare ecology cycle. Integr Environ Assess Manag 2023;00:1-9. Published 2023. This article is a US Government work and is in the public domain in the USA. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).
To evaluate the difference in postoperative pain scores of dogs undergoing abdominal surgery receiving surgical incision infiltration of saline or bupivacaine liposomal injectable suspension (BLIS).
...40 dogs undergoing exploratory laparotomy.
Dogs were prospectively enrolled and randomized to receive either BLIS or saline surgical incision infiltration. All dogs received 5.3 mg of BLIS/kg or an equal volume of saline infiltrated in the muscle/fascia, subcutaneous tissue, and intradermal layer during closure. All dogs received a standardized postoperative pain management protocol. Pain assessment was performed at select time points postoperatively by blinded observers with an electronic algometer, short version of the Glasgow Composite Measure Pain Scale (GCMPS), and indirect measures of pain, including systolic blood pressure, heart rate, and serum cortisol levels.
At day 0, blood pressure was higher in the saline group (149.6 vs 125.8 mm Hg; P = .006). At day 3, GCMPS was lower in the BLIS group (BLIS = 1, saline = 2, P = .027), though both average GCMPS scores were low and only 10 dogs were available for day 3 assessments (6 BLIS and 4 saline). No other differences in algometer readings, GCMPS scores, other measured parameters, or need for rescue analgesia were present between BLIS and saline groups at any time point. There was no difference in postoperative incisional infection rate or complications.
Use of BLIS for exploratory laparotomy did not provide improved pain control over postoperative opioid administration alone. Patients that received BLIS had no increase in short-term complications.
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