The landforms of northern Gale crater on Mars expose thick sequences of sedimentary rocks. Based on images obtained by the Curiosity rover, we interpret these outcrops as evidence for past fluvial, ...deltaic, and lacustrine environments. Degradation of the crater wall and rim probably supplied these sediments, which advanced inward from the wall, infilling both the crater and an internal lake basin to a thickness of at least 75 meters. This intracrater lake system probably existed intermittently for thousands to millions of years, implying a relatively wet climate that supplied moisture to the crater rim and transported sediment via streams into the lake basin. The deposits in Gale crater were then exhumed, probably by wind-driven erosion, creating Aeolis Mons (Mount Sharp).
The Integrated Science Investigation of the Sun (ISIS) is a complete science investigation on the Solar Probe Plus (SPP) mission, which flies to within nine solar radii of the Sun’s surface. ISIS ...comprises a two-instrument suite to measure energetic particles over a very broad energy range, as well as coordinated management, science operations, data processing, and scientific analysis. Together, ISIS observations allow us to explore the mechanisms of energetic particles dynamics, including their: (1) Origins—defining the seed populations and physical conditions necessary for energetic particle acceleration; (2) Acceleration—determining the roles of shocks, reconnection, waves, and turbulence in accelerating energetic particles; and (3) Transport—revealing how energetic particles propagate from the corona out into the heliosphere. The two ISIS Energetic Particle Instruments measure lower (EPI-Lo) and higher (EPI-Hi) energy particles. EPI-Lo measures ions and ion composition from ∼20 keV/nucleon–15 MeV total energy and electrons from ∼25–1000 keV. EPI-Hi measures ions from ∼1–200 MeV/nucleon and electrons from ∼0.5–6 MeV. EPI-Lo comprises 80 tiny apertures with fields-of-view (FOVs) that sample over nearly a complete hemisphere, while EPI-Hi combines three telescopes that together provide five large-FOV apertures. ISIS observes continuously inside of 0.25 AU with a high data collection rate and burst data (EPI-Lo) coordinated with the rest of the SPP payload; outside of 0.25 AU, ISIS runs in low-rate science mode whenever feasible to capture as complete a record as possible of the solar energetic particle environment and provide calibration and continuity for measurements closer in to the Sun. The ISIS Science Operations Center plans and executes commanding, receives and analyzes all ISIS data, and coordinates science observations and analyses with the rest of the SPP science investigations. Together, ISIS’ unique observations on SPP will enable the discovery, untangling, and understanding of the important physical processes that govern energetic particles in the innermost regions of our heliosphere, for the first time. This paper summarizes the ISIS investigation at the time of the SPP mission Preliminary Design Review in January 2014.
The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating ...mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit ...the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.
Lake 227, a small lake in the Precambrian Shield at the Experimental Lakes Area (ELA), has been fertilized for 37 years with constant annual inputs of phosphorus and decreasing inputs of nitrogen to ...test the theory that controlling nitrogen inputs can control eutrophication. For the final 16 years (1990-2005), the lake was fertilized with phosphorus alone. Reducing nitrogen inputs increasingly favored nitrogen-fixing cyanobacteria as a response by the phytoplankton community to extreme seasonal nitrogen limitation. Nitrogen fixation was sufficient to allow biomass to continue to be produced in proportion to phosphorus, and the lake remained highly eutrophic, despite showing indications of extreme nitrogen limitation seasonally. To reduce eutrophication, the focus of management must be on decreasing inputs of phosphorus.
Pancreatic ductal adenocarcinoma (PDAC) evolves a complex microenvironment comprised of multiple cell types, including pancreatic stellate cells (PSC). Previous studies have demonstrated that stromal ...supply of alanine, lipids, and nucleotides supports the metabolism, growth, and therapeutic resistance of PDAC. Here we demonstrate that alanine cross-talk between PSCs and PDAC is orchestrated by the utilization of specific transporters. PSCs utilize SLC1A4 and other transporters to rapidly exchange and maintain environmental alanine concentrations. Moreover, PDAC cells upregulate SLC38A2 to supply their increased alanine demand. Cells lacking SLC38A2 fail to concentrate intracellular alanine and undergo a profound metabolic crisis resulting in markedly impaired tumor growth. Our results demonstrate that stromal-cancer metabolic niches can form through differential transporter expression, creating unique therapeutic opportunities to target metabolic demands of cancer. SIGNIFICANCE: This work identifies critical neutral amino acid transporters involved in channeling alanine between pancreatic stellate and PDAC cells. Targeting PDAC-specific alanine uptake results in a metabolic crisis impairing metabolism, proliferation, and tumor growth. PDAC cells specifically activate and require SLC38A2 to fuel their alanine demands that may be exploited therapeutically.
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Apicomplexan parasites are auxotrophic for a range of amino acids which must be salvaged from their host cells, either through direct uptake or degradation of host proteins. Here, we describe a ...family of plasma membrane-localized amino acid transporters, termed the Apicomplexan Amino acid Transporters (ApiATs), that are ubiquitous in apicomplexan parasites. Functional characterization of the ApiATs of Toxoplasma gondii indicate that several of these transporters are important for intracellular growth of the tachyzoite stage of the parasite, which is responsible for acute infections. We demonstrate that the ApiAT protein TgApiAT5-3 is an exchanger for aromatic and large neutral amino acids, with particular importance for L-tyrosine scavenging and amino acid homeostasis, and that TgApiAT5-3 is critical for parasite virulence. Our data indicate that T. gondii expresses additional proteins involved in the uptake of aromatic amino acids, and we present a model for the uptake and homeostasis of these amino acids. Our findings identify a family of amino acid transporters in apicomplexans, and highlight the importance of amino acid scavenging for the biology of this important phylum of intracellular parasites.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Context
Cotadutide is a dual receptor agonist with balanced glucagon-like peptide-1 and glucagon activity.
Objective
To evaluate different doses of cotadutide and investigate underlying ...mechanisms for its glucose-lowering effects.
Design/setting
Randomized, double-blind, phase 2a study conducted in 2 cohorts at 5 clinical trial sites.
Patients
Participants were 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs.
Intervention
Once-daily subcutaneous cotadutide or placebo for 49 days. Doses (50–300 µg) were uptitrated weekly (cohort 1) or biweekly (cohort 2).
Main outcome measures
Co-primary end points (cohort 1) were percentage changes from baseline to end of treatment in glucose (area under the curve from 0 to 4 hours AUC0–4h) post–mixed-meal tolerance test (MMTT) and weight. Exploratory measures included postprandial insulin and gastric emptying time (GET; cohort 2).
Results
Patients received cotadutide (cohort 1, n = 26; cohort 2, n = 20) or placebo (cohort 1, n = 13; cohort 2, n = 6). Significant reductions were observed with cotadutide vs placebo in glucose AUC0–4h post MMTT (least squares mean 90% CI, −21.52% −25.68, −17.37 vs 6.32% 0.45, 12.20; P < 0.001) and body weight (−3.41% −4.37, −2.44 vs −0.08% −1.45, 1.28; P = 0.002). A significant increase in insulin AUC0–4h post MMTT was observed with cotadutide (19.3 mU.h/L 5.9, 32.6; P = 0.008) and GET was prolonged on day 43 with cotadutide vs placebo (t½: 117.2 minutes vs −42.9 minutes; P = 0.0392).
Conclusion
These results suggest that the glucose-lowering effects of cotadutide are mediated by enhanced insulin secretion and delayed gastric emptying.
Trial Registration
ClinicalTrials.gov, NCT03244800.
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