Very recently the NICER collaboration published the first-ever accurate measurement of mass and radius together for PSR J0030+0451, a nearby isolated quickly rotating neutron star (NS). In this work ...we set the joint constraints on the equation of state (EoS) and some bulk properties of NSs with the data of PSR J0030+0451, GW170817, and some nuclear experiments. The piecewise polytropic expansion method and the spectral decomposition method have been adopted to parameterize the EoS. The resulting constraints are consistent with each other. Assuming the maximal gravitational mass of nonrotating NS MTOV lies between 2.04M and 2.4M , with the piecewise method the pressure at twice nuclear saturation density is measured to be at the 90% level. For an NS with canonical mass of 1.4M , we have the moment of inertia , tidal deformability , radius , and binding energy at the 90% level, which are improved in comparison to the constraints with the sole data of GW170817. These conclusions are drawn for the mass/radius measurements of PSR J0030+0451 by Riley et al. For the measurements of Miller et al., the results are rather similar.
Abstract In 2019, the Neutron star Interior Composition ExploreR (NICER) mission released its findings on the mass and radius of the isolated neutron star (INS) PSR J0030+0451, revealing a mass of ...approximately 1.4 solar masses ( M ⊙ ) and a radius near 13 km. However, the recent reanalysis by the NICER collaboration suggests that the available data primarily yield a precise inference of the compactness for this source while the resulting mass and radius are strongly model-dependent and diverse (the 68.3% credible regions just overlap slightly for the ST+PDT and PDT-U models). By integrating this compactness data with the equation of state (EOS) refined by our latest investigations, we have deduced the mass and radius for PSR J0030+0451, delivering estimates of M = 1.48 − 0.10 + 0.09 M ⊙ and R = 12.38 − 0.70 + 0.51 km for the compactness found in the ST+PDT model, alongside M = 1.47 − 0.20 + 0.14 M ⊙ and R = 12.37 − 0.69 + 0.50 km for the compactness in the PDT-U model. These two groups of results are well consistent with each other and the direct X-ray data inference within the ST+PDT model seems to be favored. Additionally, we have calculated the tidal deformability, moment of inertia, and gravitational binding energy for this neutron star. Furthermore, employing these refined EOS models, we have updated mass–radius estimates for three INSs with established gravitational redshifts.
Starting from metal oxides, B4C and graphite, a suite of high-entropy boride ceramics, formulated (Hf0.2Zr0.2Ta0.2Nb0.2Ti0.2)B2, (Hf0.2Zr0.2Mo0.2Nb0.2Ti0.2)B2 and (Hf0.2Mo0.2Ta0.2Nb0.2Ti0.2)B2 ...derived from boro/carbothermal reduction at 1600 °C were fabricated by spark plasma sintering at 2000 °C. It was found that the synthetic high-entropy boride crystalized in hexagonal structure and the yield of the targeting phase was calculated to be over 93.0 wt% in the sintered ceramics. Benefitting from the nearly full densification (96.3% ˜ 98.5% in relative density) and the refined microstructure, the products exhibited the relatively high Vickers hardness. The indentation fracture toughness was determined to be comparable with the single transition metal-diboride ceramics. It should be noted that the formation of high-entropy boride ceramics were featured with the relatively high hardness at no expense of the fracture toughness.
As one of the most successful therapeutic target families, G protein-coupled receptors (GPCRs) have experienced a transformation from random ligand screening to knowledge-driven drug design. We are ...eye-witnessing tremendous progresses made recently in the understanding of their structure-function relationships that facilitated drug development at an unprecedented pace. This article intends to provide a comprehensive overview of this important field to a broader readership that shares some common interests in drug discovery.
Glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor that plays an important role in glucose homeostasis and treatment of type 2 diabetes. Structures of full-length class ...B receptors were determined in complex with their orthosteric agonist peptides, however, little is known about their extracellular domain (ECD) conformations in the absence of orthosteric ligands, which has limited our understanding of their activation mechanism. Here, we report the 3.2 Å resolution, peptide-free crystal structure of the full-length human GLP-1R in an inactive state, which reveals a unique closed conformation of the ECD. Disulfide cross-linking validates the physiological relevance of the closed conformation, while electron microscopy (EM) and molecular dynamic (MD) simulations suggest a large degree of conformational dynamics of ECD that is necessary for binding GLP-1. Our inactive structure represents a snapshot of the peptide-free GLP-1R and provides insights into the activation pathway of this receptor family.
The aim of this study is to validate the Global Leadership Initiative on Malnutrition (GLIM) criteria and determine the number of Nutritional Risk Screening 2002 (NRS2002)–positive patients who do ...not meet the GLIM, as well as examine whether these patients would benefit from nutritional support therapy.
A reanalysis of a published prospective observational study was performed. The subjects were rediagnosed per the NRS2002 and GLIM criteria. The prevalence of malnutrition was reported, and the difference in rate of infection complications and total complications between the nutritional support therapy and glucose-electrolyte cohorts was calculated.
Among 1831 cases in the original database, 827 cases (45.2%) were NRS2002-positive. A total of 391 cases were identified by the GLIM criteria as malnourished (21.4%) and of these, subjects in the nutritional support therapy cohort had fewer infection complications than those in the glucose-electrolyte cohort (13.0% vs. 23.0%; P = 0.010). The remaining 436 patients were NRS2002 positive but GLIM negative (23.8%). The rate of infection was also significantly lower in the support cohort than in the nonsupport cohort (8.0% vs. 15.7%; P = 0.011). Nutritional support was proven o be a protective factor for infection complications in both GLIM-positive (odds ratio: 0.407; 95% confidence interval, 0.232–0.714; P = 0.002) and NRS2002-positive/GLIM-negative patients odds ratio: 0.314; 95% confidence interval, 0.161–0.612; P = 0.001).
The GLIM criteria have been validated, and are useful in identifying malnourished patients who may have fewer infection complications due to nutritional support therapy. However, the criteria neglected half of the patients identified by NRS2002, among whom nutritional support therapy also decreased the rate of infection complications.
•Global Leadership Initiative on Malnutrition (GLIM) criteria are a new consensus to diagnosis malnutrition, but needs validation•Nutritional Risk Screening 2002 (NRS2002) can be used as the first screening step of the GLIM criteria•NRS2002-positive patients have fewer infections due to nutritional support•Nutrition support reduces infection rates in malnourished patients, as determined by the GLIM criteria•Patients who are NRS2002 positive but GLIM negative also benefit from nutritional support
The parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to calcium homeostasis and a therapeutic target for osteoporosis and hypoparathyroidism. Here we report the ...cryo-electron microscopy structure of human PTH1R bound to a long-acting PTH analog and the stimulatory G protein. The bound peptide adopts an extended helix with its amino terminus inserted deeply into the receptor transmembrane domain (TMD), which leads to partial unwinding of the carboxyl terminus of transmembrane helix 6 and induces a sharp kink at the middle of this helix to allow the receptor to couple with G protein. In contrast to a single TMD structure state, the extracellular domain adopts multiple conformations. These results provide insights into the structural basis and dynamics of PTH binding and receptor activation.
Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to ...prevent cancer progression. We aimed to determine whether blocking extracellular ATP-P2RY2 axis could be a potential therapeutic approach for PDAC treatment.
Expression of P2RY2 was determined in 264 human PDAC samples and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity, and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression.
P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT-mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevated expression of c-Myc and HIF1α, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacologic inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. In addition, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice.
These findings reveal the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.
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