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Cancer stem cells (CSCs) are inherently resistant to chemotherapy, and CSCs in chemotherapy-failed recurrent tumors are enriched; however, the cellular origin of chemotherapy-induced CSC enrichment remains unclear. Communication with stromal fibroblasts may induce cancer cell dedifferentiation into CSCs through secreted factors. We recently demonstrated that fibroblast-derived exosomes promote chemoresistance in colorectal cancer (CRC). Here, we report that fibroblasts confer CRC chemoresistance via exosome-induced reprogramming (dedifferentiation) of bulk CRC cells to phenotypic and functional CSCs. At the molecular level, we provided evidence that the major reprogramming regulators in fibroblast-exosomes are Wnts. Exosomal Wnts were found to increase Wnt activity and drug resistance in differentiated CRC cells, and inhibiting Wnt release diminished this effect in vitro and in vivo. Together, our results indicate that exosomal Wnts derived from fibroblasts could induce the dedifferentiation of cancer cells to promote chemoresistance in CRC, and suggest that interfering with exosomal Wnt signaling may help to improve chemosensitivity and the therapeutic window.

Double neutron star (DNS) merger events are promising candidates of short gamma-ray burst (sGRB) progenitors as well as high-frequency gravitational wave (GW) emitters. On August 17, 2017, such a coinciding event was detected by both the LIGO-Virgo gravitational wave detector network as GW170817 and Gamma-Ray Monitor on board NASA’s Fermi Space Telescope as GRB 170817A. Here, we show that the fluence and spectral peak energy of this sGRB fall into the lower portion of the distributions of known sGRBs. Its peak isotropic luminosity is abnormally low. The estimated event rate density above this luminosity is at least 19 0 - 160 + 440  Gpc −3  yr −1 , which is close to but still below the DNS merger event rate density. This event likely originates from a structured jet viewed from a large viewing angle. There are similar faint soft GRBs in the Fermi archival data, a small fraction of which might belong to this new population of nearby, low-luminosity sGRBs. A short-duration gamma-ray burst was detected along with a double neutron start merger gravitational wave by LIGO-Virgo on August 17th 2017. Here, the authors show that the fluence and spectral peak energy of this event fall into the lower portion of the distribution of known short-duration gamma-ray bursts.

Gamma-ray bursts (GRBs) are flashes of high-energy radiation arising from energetic cosmic explosions. Bursts of long (greater than two seconds) duration are produced by the core-collapse of massive stars 1 , and those of short (less than two seconds) duration by the merger of compact objects, such as two neutron stars 2 . A third class of events with hybrid high-energy properties was identified 3 , but never conclusively linked to a stellar progenitor. The lack of bright supernovae rules out typical core-collapse explosions 4 – 6 , but their distance scales prevent sensitive searches for direct signatures of a progenitor system. Only tentative evidence for a kilonova has been presented 7 , 8 . Here we report observations of the exceptionally bright GRB 211211A, which classify it as a hybrid event and constrain its distance scale to only 346 megaparsecs. Our measurements indicate that its lower-energy (from ultraviolet to near-infrared) counterpart is powered by a luminous (approximately 10 42  erg per second) kilonova possibly formed in the ejecta of a compact object merger. A bright, long-duration gamma-ray burst observed by the Swift observatory has hybrid high-energy properties, suggesting that its origin is the merger of a compact binary.

Nanocrystals of apatitic calcium phosphate impart the organic-inorganic nanocomposite in bone with favorable mechanical properties. So far, the factors preventing crystal growth beyond the favorable thickness of ca. 3 nm have not been identified. Here we show that the apatite surfaces are studded with strongly bound citrate molecules, whose signals have been identified unambiguously by multinuclear magnetic resonance (NMR) analysis. NMR reveals that bound citrate accounts for 5.5 wt% of the organic matter in bone and covers apatite at a density of about 1 molecule per (2 nm)², with its three carboxylate groups at distances of 0.3 to 0.45 nm from the apatite surface. Bound citrate is highly conserved, being found in fish, avian, and mammalian bone, which indicates its critical role in interfering with crystal thickening and stabilizing the apatite nanocrystals in bone.

Gamma-ray bursts (GRBs) have been phenomenologically classified into long and short populations based on the observed bimodal distribution of duration 1 . Multi-wavelength and multi-messenger observations in recent years have revealed that in general long GRBs originate from massive star core collapse events 2 , whereas short GRBs originate from binary neutron star mergers 3 . It has been known that the duration criterion is sometimes unreliable, and multi-wavelength criteria are needed to identify the physical origin of a particular GRB 4 . Some apparently long GRBs have been suggested to have a neutron star merger origin 5 , whereas some apparently short GRBs have been attributed to genuinely long GRBs 6 whose short, bright emission is slightly above the detector’s sensitivity threshold. Here, we report the comprehensive analysis of the multi-wavelength data of the short, bright GRB 200826A. Characterized by a sharp pulse, this burst shows a duration of 1 second and no evidence of an underlying longer-duration event. Its other observational properties such as its spectral behaviours, total energy and host galaxy offset are, however, inconsistent with those of other short GRBs believed to originate from binary neutron star mergers. Rather, these properties resemble those of long GRBs. This burst confirms the existence of short-duration GRBs with stellar core-collapse origin 4 , and presents some challenges to the existing models. A gamma-ray burst (GRB) is reported to show a sharp 1-second spike, characteristic of short GRBs, but with other observational properties resembling those of long GRBs. This burst may belong to a class of core-collapse-origin GRBs with genuinely short durations.

The +0.1‰ elevated 56 Fe/ 54 Fe ratio of terrestrial basalts relative to chondrites was proposed to be a fingerprint of core-mantle segregation. However, the extent of iron isotopic fractionation between molten metal and silicate under high pressure–temperature conditions is poorly known. Here we show that iron forms chemical bonds of similar strengths in basaltic glasses and iron-rich alloys, even at high pressure. From the measured mean force constants of iron bonds, we calculate an equilibrium iron isotope fractionation between silicate and iron under core formation conditions in Earth of ∼0–0.02‰, which is small relative to the +0.1‰ shift of terrestrial basalts. This result is unaffected by small amounts of nickel and candidate core-forming light elements, as the isotopic shifts associated with such alloying are small. This study suggests that the variability in iron isotopic composition in planetary objects cannot be due to core formation. Terrestrial basalts have a unique iron isotopic signature taken as fingerprints of core formation. Here, high pressure studies show that force constants of iron bonds increase with pressure similarly for silicate and metals suggesting interplanetary isotopic variability is not due to core formation.

While oral antidepressants reach efficacy after weeks, single-dose intravenous (i.v.) ketamine has rapid, yet time-limited antidepressant effects. We aimed to determine the efficacy and safety of single-dose i.v. ketamine augmentation of escitalopram in major depressive disorder (MDD). Thirty outpatients with severe MDD (17-item Hamilton Rating Scale for Depression total score ⩾ 24) were randomized to 4 weeks double-blind treatment with escitalopram 10 mg/day+single-dose i.v. ketamine (0.5 mg/kg over 40 min) or escitalopram 10 mg/day + placebo (0.9% i.v. saline). Depressive symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR). Suicidal ideation was evaluated with the QIDS-SR item 12. Adverse psychopathological effects were measured with the Brief Psychiatric Rating Scale (BPRS)-positive symptoms, Young Mania Rating Scale (YMRS) and Clinician Administered Dissociative States Scale (CADSS). Patients were assessed at baseline, 1, 2, 4, 24 and 72 h and 7, 14, 21 and 28 days. Time to response (⩾ 50% MADRS score reduction) was the primary outcome. By 4 weeks, more escitalopram + ketamine-treated than escitalopram + placebo-treated patients responded (92.3% v. 57.1%, p = 0.04) and remitted (76.9% v. 14.3%, p = 0.001), with significantly shorter time to response [hazard ratio (HR) 0.04, 95% confidence interval (CI) 0.01-0.22, p < 0.001] and remission (HR 0.11, 95% CI 0.02-0.63, p = 0.01). Compared to escitalopram + placebo, escitalopram + ketamine was associated with significantly lower MADRS scores from 2 h to 2 weeks [(peak = 3 days-2 weeks; effect size (ES) = 1.08-1.18)], QIDS-SR scores from 2 h to 2 weeks (maximum ES = 1.27), and QIDS-SR suicidality from 2 to 72 h (maximum ES = 2.24). Only YMRS scores increased significantly with ketamine augmentation (1 and 2 h), without significant BPRS or CADSS elevation. Single-dose i.v. ketamine augmentation of escitalopram was safe and effective in severe MDD, holding promise for speeding up early oral antidepressant efficacy.

BACKGROUND: Neutrophil gelatinase–associated lipocalin (NGAL) is released from renal tubular cells after injury and serves in humans as a real‐time indicator of active kidney damage, including acute kidney injury (AKI) and chronic kidney disease (CKD). However, NGAL concentrations in dogs with naturally occurring AKI or CKD rarely have been explored in detail. HYPOTHESIS/OBJECTIVES: The goal of this study was to evaluate whether NGAL can serve as a useful biomarker in dogs with naturally occurring renal disease. ANIMALS: Client‐owned dogs with renal disease (57) and control dogs without any disease (12) were examined. METHODS: Serum NGAL (sNGAL) and urine NGAL (uNGAL) concentrations were measured in each animal by a newly developed ELISA system. Demographic, hematologic, and serum biochemical data were recorded. Survival attributable to AKI and CKD was evaluated at 30 days and 90 days, respectively. RESULTS: Serum and urine NGAL concentrations in azotemic dogs were significantly higher than in nonazotemic dogs and were highly correlated with serum creatinine concentration (P < .05). Among CKD dogs, death was associated with significantly higher sNGAL and uNGAL concentrations compared with survivors. Receiver‐operating characteristic curve (ROC) analysis showed that sNGAL was better than serum creatinine concentration when predicting clinical outcomes for CKD dogs (P < .05). The best cutoff point for sNGAL was 50.6 ng/mL, which gave a sensitivity and a specificity of 76.9 and 100%, respectively. Furthermore, dogs that had higher concentrations of sNGAL survived for a significantly shorter time. CONCLUSION: sNGAL is a useful prognostic marker when evaluating dogs with CKD.

Spatial patterns in trait variation reflect underlying community assembly processes, allowing us to test hypotheses about their trait and environmental drivers by identifying the strongest correlates of characteristic spatial patterns. For 43 evergreen tree species (> 1cm dbh) in a 20 ha seasonal tropical rainforest plot in Xishuangbanna, China, we compared the ability of drought tolerance traits, other physiological traits and commonly measured functional traits to predict the spatial patterns expected from the assembly processes of habitat associations, niche overlap-based competition, and hierarchical competition. We distinguished the neighborhood-scale (0- 20m) patterns expected from competition from larger-scale habitat associations with a wavelet method. Species' drought tolerance and habitat variables related to soil water supply were strong drivers of habitat associations, and drought tolerance showed a significant spatial signal for influencing competition. Overall, the traits most strongly associated with habitat, as quantified using multivariate models, were leaf density, leaf turgor loss point (πtlp; also known as the leaf wilting point), and stem hydraulic conductivity (r2 range for the best fit models = 0.27-0.36). At neighborhood scales, species spatial associations were positively correlated with similarity in πtlp, consistent with predictions for hierarchical competition. Although the correlation between πtlp and interspecific spatial associations was weak (r2 < 0.01), this showed a persistent influence of drought tolerance on neighborhood interactions and community assembly. Quantifying the full impact of traits on competitive interactions in forests may require incorporating plasticity among individuals within species, especially among specific life stages, and moving beyond individual traits to integrate the impact of multiple traits on whole-plant performance and resource demand.

Internal tandem duplication (ITD) mutation in Fms-like tyrosine kinase 3 gene (FLT3/ITD) represents an unfavorable genetic change in acute myeloid leukemia (AML) and is associated with poor prognosis. Metabolic alterations have been involved in tumor progression and attracted interest as a target for therapeutic intervention. However, few studies analyzed the adaptations of cellular metabolism in the context of FLT3/ITD mutation. Here, we report that FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity. Inhibition of glycolysis preferentially causes severe ATP depletion and massive cell death in FLT3/ITD leukemia cells. Glycolytic inhibitors significantly enhances the cytotoxicity induced by FLT3 tyrosine kinase inhibitor sorafenib. Importantly, such combination provides substantial therapeutic benefit in a murine model bearing FLT3/ITD leukemia. Our study suggests that FLT3/ITD mutation promotes Warburg effect, and such metabolic alteration can be exploited to develop effective therapeutic strategy for treatment of AML with FLT3/ITD mutation via metabolic intervention.