Significance Here we report a fundamental and previously unknown role for the receptor tyrosine kinase AXL as a direct hypoxia-inducible transcription factor target driving the aggressive phenotype ...in renal clear cell carcinoma through the regulation of the SRC proto-oncogene nonreceptor tyrosine kinase and the MET proto-oncogene receptor tyrosine kinase. Of therapeutic relevance, we demonstrate that inactivation of growth arrest-specific 6 (GAS6)/AXL signaling using a soluble AXL decoy receptor reversed the invasive and metastatic phenotype of clear cell renal cell carcinoma (ccRCC) cells. Furthermore, we define a pathway by which GAS6/AXL signaling utilizes lateral activation of MET through SRC to maximize cellular invasion. Our data provide an alternative model for SRC and MET activation by GAS6 in ccRCC and identify AXL as a therapeutic target driving the aggressive phenotype in renal clear cell carcinoma.
The genetic heterogeneity of cancer influences the trajectory of tumor progression and may underlie clinical variation in therapy response. To model such heterogeneity, we produced genetically and ...pathologically accurate mouse models of common forms of human acute myeloid leukemia (AML) and developed methods to mimic standard induction chemotherapy and efficiently monitor therapy response. We see that murine AMLs harboring two common human AML genotypes show remarkably diverse responses to conventional therapy that mirror clinical experience. Specifically, murine leukemias expressing the AML1/ETO fusion oncoprotein, associated with a favorable prognosis in patients, show a dramatic response to induction chemotherapy owing to robust activation of the p53 tumor suppressor network. Conversely, murine leukemias expressing MLL fusion proteins, associated with a dismal prognosis in patients, are drug-resistant due to an attenuated p53 response. Our studies highlight the importance of genetic information in guiding the treatment of human AML, functionally establish the p53 network as a central determinant of chemotherapy response in AML, and demonstrate that genetically engineered mouse models of human cancer can accurately predict therapy response in patients.
Human and veterinarian pharmaceuticals have been detected in the aquatic environment for a number of years, but the potential for biological effects in exposed aquatic organism is only now being ...reported. The lipid regulator, gemfibrozil (GEM) is detected at μg/L concentrations in domestic wastewater and ng/L concentrations in surface waters. We investigated the uptake of GEM in goldfish (
Carassius auratus) over a 96
h time period by measuring GEM in blood plasma using LC–MS/MS. Results indicated that GEM can be taken up from water through the gills. In goldfish exposed to GEM by a single intraperitoneal injection, concentrations of GEM in the blood plasma declined rapidly over 96
h post-injection, with a half-life estimated at approximately 19
h.
Exposure of goldfish to waterborne GEM at an environmentally relevant concentration over 14 days resulted in a plasma bioconcentration factor of 113. In goldfish exposed to aqueous concentrations of GEM for 96
h or 14 days, plasma testosterone (T) was reduced by over 50% in fish from all treatments. As a possible mechanistic explanation for the observed reduction in T, levels of steroid acute regulatory (StAR) protein transcript in goldfish testes were assessed by RT–PCR. StAR protein is involved in the transport of cholesterol from the outer to the inner mitochondrial membrane for transformation by the first enzyme in steroidogenesis. After exposure to GEM for 96
h, a 50% decrease in StAR mRNA levels was observed in goldfish. Gonadal StAR mRNA levels were not affected in the 14 days exposure, indicating that the observed decreases in plasma testosterone were not solely due to impaired delivery of cholesterol to the inner mitochondrial membrane. Our results demonstrate that exposure to environmental levels of GEM leads to bioconcentration of the drug in plasma and the potential for endocrine disruption in fish.
The citric acid cycle is central to the regulation of energy homeostasis and cell metabolism. Mutations in enzymes that catalyse steps in the citric acid cycle result in human diseases with various ...clinical presentations. The intermediates of the citric acid cycle are present at micromolar concentration in blood and are regulated by respiration, metabolism and renal reabsorption/extrusion. Here we show that GPR91 (ref. 3), a previously orphan G-protein-coupled receptor (GPCR), functions as a receptor for the citric acid cycle intermediate succinate. We also report that GPR99 (ref. 4), a close relative of GPR91, responds to α-ketoglutarate, another intermediate in the citric acid cycle. Thus by acting as ligands for GPCRs, succinate and α-ketoglutarate are found to have unexpected signalling functions beyond their traditional roles. Furthermore, we show that succinate increases blood pressure in animals. The succinate-induced hypertensive effect involves the renin-angiotensin system and is abolished in GPR91-deficient mice. Our results indicate a possible role for GPR91 in renovascular hypertension, a disease closely linked to atherosclerosis, diabetes and renal failure.
Abstract We observe systematic profile changes in the visible pulsar of the compact double neutron star system PSR J1946+2052 using observations with the Five-hundred-meter Aperture Spherical radio ...Telescope (FAST). The interpulse of PSR J1946+2052 changed from a single-peak to a double-peak shape from 2018–2021. We attribute this evolution as the result of the relativistic spin precession of the pulsar. With the high sensitivity of FAST, we also measure significant polarization for the first time, allowing us to model this with the precessional rotating vector model. Assuming, to the first order, a circular hollow-cone-like emission beam pattern and taking the validity of general relativity (GR), we derive the binary’s orbital inclination angle ( 63 ∘ − 3 ∘ + 5 ∘ ) and pulsar’s spin geometry. The pulsar’s spin vector and the orbital angular momentum vector are found to be only slightly misaligned ( 0. ∘ 21 − 0. ∘ 10 + 0. ∘ 28 ). The quoted uncertainties do not reflect the systematic uncertainties introduced by our model assumptions. By simulating future observations of profile and polarization evolution, we estimate that we could constrain the precession rate within a 43% uncertainty in 9 yr. Hence, we suggest that the system’s profile evolution could be combined with precise pulsar timing to test GR in the future.
This article describes motion planning networks (MPNet), a computationally efficient, learning-based neural planner for solving motion planning problems.MPNet uses neural networks to learn general ...near-optimal heuristics for path planning in seen and unseen environments. It takes environment information such as raw point cloud from depth sensors, as well as a robot's initial and desired goal configurations and recursively calls itself to bidirectionally generate connectable paths. In addition to finding directly connectable and near-optimal paths in a single pass, we show that worst-case theoretical guarantees can be proven if we merge this neural network strategy with classical sample-based planners in a hybrid approach while still retaining significant computational and optimality improvements. To train the MPNet models, we present an active continual learning approach that enables MPNet to learn from streaming data and actively ask for expert demonstrations when needed, drastically reducing data for training. We validate MPNet against gold-standard and state-of-the-art planning methods in a variety of problems from two-dimensional to seven-dimensional robot configuration spaces in challenging and cluttered environments, with results showing significant and consistently stronger performance metrics, and motivating neural planning in general as a modern strategy for solving motion planning problems efficiently.
Objective
Changes in gut microbiota have been linked to systemic lupus erythematosus (SLE), but knowledge is limited. Our study aimed to provide an in‐depth understanding of the contribution of gut ...microbiota to the immunopathogenesis of SLE.
Methods
Fecal metagenomes from 117 patients with untreated SLE and 52 SLE patients posttreatment were aligned with 115 matched healthy controls and analyzed by whole‐genome profiling. For comparison, we assessed the fecal metagenome of MRL/lpr mice. The oral microbiota origin of the gut species that existed in SLE patients was documented by single‐nucleotide polymorphism–based strain‐level analyses. Functional validation assays were performed to demonstrate the molecular mimicry of newly found microbial peptides.
Results
Gut microbiota from individuals with SLE displayed significant differences in microbial composition and function compared to healthy controls. Certain species, including the Clostridium species ATCC BAA‐442 as well as Atopobium rimae, Shuttleworthia satelles, Actinomyces massiliensis, Bacteroides fragilis, and Clostridium leptum, were enriched in SLE gut microbiota and reduced after treatment. Enhanced lipopolysaccharide biosynthesis aligned with reduced branched chain amino acid biosynthesis was observed in the gut of SLE patients. The findings in mice were consistent with our findings in human subjects. Interestingly, some species with an oral microbiota origin were enriched in the gut of SLE patients. Functional validation assays demonstrated the proinflammatory capacities of some microbial peptides derived from SLE‐enriched species.
Conclusion
This study provides detailed information on the microbiota of untreated patients with SLE, including their functional signatures, similarities with murine counterparts, oral origin, and the definition of autoantigen‐mimicking peptides. Our data demonstrate that microbiome‐altering approaches may offer valuable adjuvant therapies in SLE.
Weyl semimetals are a class of materials that can be regarded as three-dimensional analogs of graphene upon breaking time-reversal or inversion symmetry. Electrons in a Weyl semimetal behave as Weyl ...fermions, which have many exotic properties, such as chiral anomaly and magnetic monopoles in the crystal momentum space. The surface state of a Weyl semimetal displays pairs of entangled Fermi arcs at two opposite surfaces. However, the existence of Weyl semimetals has not yet been proved experimentally. Here, we report the experimental realization of a Weyl semimetal in TaAs by observing Fermi arcs formed by its surface states using angle-resolved photoemission spectroscopy. Our first-principles calculations, which match remarkably well with the experimental results, further confirm that TaAs is a Weyl semimetal.
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