Cancer associated fibroblasts (CAFs) are key stroma cells that play dominant roles in tumor progression. However, the CAFs-derived molecular determinants that regulate colorectal cancer (CRC) ...metastasis and chemoresistance have not been fully characterized.
CAFs and NFs were obtained from fresh CRC and adjacent normal tissues. Exosomes were isolated from conditioned medium and serum of CRC patients using ultracentrifugation method and ExoQuick Exosome Precipitation Solution kit, and characterized by transmission electronic microscopy, nanosight and western blot. MicroRNA microarray was employed to identify differentially expressed miRNAs in exosomes secreted by CAFs or NFs. The internalization of exosomes, transfer of miR-92a-3p was observed by immunofluorescence. Boyden chamber migration and invasion, cell counting kit-8, flow cytometry, plate colony formation, sphere formation assays, tail vein injection and primary colon cancer liver metastasis assays were employed to explore the effect of NFs, CAFs and exosomes secreted by them on epithelial-mesenchymal transition, stemness, metastasis and chemotherapy resistance of CRC. Luciferase report assay, real-time qPCR, western blot, immunofluorescence, and immunohistochemistry staining were employed to explore the regulation of CRC metastasis and chemotherapy resistance by miR-92a-3p, FBXW7 and MOAP1.
CAFs promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resistance of CRC cells. Importantly, CAFs exert their roles by directly transferring exosomes to CRC cells, leading to a significant increase of miR-92a-3p level in CRC cells. Mechanically, increased expression of miR-92a-3p activates Wnt/β-catenin pathway and inhibits mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1, contributing to cell stemness, EMT, metastasis and 5-FU/L-OHP resistance in CRC. Clinically, miR-92a-3p expression is significantly increased in CRC tissues and negatively correlated with the levels of FBXW7 and MOAP1 in CRC specimens, and high expression of exosomal miR-92a-3p in serum was highly linked with metastasis and chemotherapy resistance in CRC patients.
CAFs secreted exosomes promote metastasis and chemotherapy resistance of CRC. Inhibiting exosomal miR-92a-3p provides an alternative modality for the prediction and treatment of metastasis and chemotherapy resistance in CRC.
We reveal the cooperative effect of coherent and dissipative magnon-photon couplings in an open cavity magnonic system, which leads to nonreciprocity with a considerably large isolation ratio and ...flexible controllability. Furthermore, we discover unidirectional invisibility for microwave propagation, which appears at the zero-damping condition for hybrid magnon-photon modes. A simple model is developed to capture the generic physics of the interference between coherent and dissipative couplings, which accurately reproduces the observations over a broad range of parameters. This general scheme could inspire methods to achieve nonreciprocity in other systems.
We report dissipative magnon-photon coupling caused by the cavity Lenz effect, where the magnons in a magnet induce a rf current in the cavity, leading to a cavity backaction that impedes the ...magnetization dynamics. This effect is revealed in our experiment as level attraction with a coalescence of hybridized magnon-photon modes, which is distinctly different from level repulsion with mode anticrossing caused by coherent magnon-photon coupling. We develop a method to control the interpolation of coherent and dissipative magnon-photon coupling, and observe a matching condition where the two effects cancel. Our work sheds light on the so-far hidden side of magnon-photon coupling, opening a new avenue for controlling and utilizing light-matter interactions.
By engineering an anti-parity-time (anti-PT ) symmetric cavity magnonics system with precise eigenspace controllability, we observe two different singularities in the same system. One type of ...singularity, the exceptional point (EP), is produced by tuning the magnon damping. Between two EPs, the maximal coherent superposition of photon and magnon states is robustly sustained by the preserved anti-PT symmetry. The other type of singularity, arising from the dissipative coupling of two antiresonances, is an unconventional bound state in the continuum (BIC). At the settings of BICs, the coupled system exhibits infinite discontinuities in the group delay. We find that both singularities coexist at the equator of the Bloch sphere, which reveals a unique hybrid state that simultaneously exhibits the maximal coherent superposition and slow light capability.
ABSTRACT
We present results from the search for a stochastic gravitational-wave background (GWB) as predicted by the theory of General Relativity using six radio millisecond pulsars from the Data ...Release 2 (DR2) of the European Pulsar Timing Array (EPTA) covering a timespan up to 24 yr. A GWB manifests itself as a long-term low-frequency stochastic signal common to all pulsars, a common red signal (CRS), with the characteristic Hellings-Downs (HD) spatial correlation. Our analysis is performed with two independent pipelines, ENTERPRISE, and TEMPONEST+FORTYTWO, which produce consistent results. A search for a CRS with simultaneous estimation of its spatial correlations yields spectral properties compatible with theoretical GWB predictions, but does not result in the required measurement of the HD correlation, as required for GWB detection. Further Bayesian model comparison between different types of CRSs, including a GWB, finds the most favoured model to be the common uncorrelated red noise described by a power law with $A = 5.13_{-2.73}^{+4.20} \times 10^{-15}$ and $\gamma = 3.78_{-0.59}^{+0.69}$ (95 per cent credible regions). Fixing the spectral index to γ = 13/3 as expected from the GWB by circular, inspiralling supermassive black hole binaries results in an amplitude of $A =2.95_{-0.72}^{+0.89} \times 10^{-15}$. We implement three different models, BAYESEPHEM, LINIMOSS, and EPHEMGP, to address possible Solar system ephemeris (SSE) systematics and conclude that our results may only marginally depend on these effects. This work builds on the methods and models from the studies on the EPTA DR1. We show that under the same analysis framework the results remain consistent after the data set extension.
Carbon cycling in the coastal zone affects global carbon budgets and is critical for understanding the urgent issues of hypoxia, acidification, and tidal wetland loss. However, there are no regional ...carbon budgets spanning the three main ecosystems in coastal waters: tidal wetlands, estuaries, and shelf waters. Here we construct such a budget for eastern North America using historical data, empirical models, remote sensing algorithms, and process‐based models. Considering the net fluxes of total carbon at the domain boundaries, 59 ± 12% (± 2 standard errors) of the carbon entering is from rivers and 41 ± 12% is from the atmosphere, while 80 ± 9% of the carbon leaving is exported to the open ocean and 20 ± 9% is buried. Net lateral carbon transfers between the three main ecosystem types are comparable to fluxes at the domain boundaries. Each ecosystem type contributes substantially to exchange with the atmosphere, with CO2 uptake split evenly between tidal wetlands and shelf waters, and estuarine CO2 outgassing offsetting half of the uptake. Similarly, burial is about equal in tidal wetlands and shelf waters, while estuaries play a smaller but still substantial role. The importance of tidal wetlands and estuaries in the overall budget is remarkable given that they, respectively, make up only 2.4 and 8.9% of the study domain area. This study shows that coastal carbon budgets should explicitly include tidal wetlands, estuaries, shelf waters, and the linkages between them; ignoring any of them may produce a biased picture of coastal carbon cycling.
Plain Language Summary
A carbon budget for a particular site or region describes the inputs and outputs of carbon to that site or region as well as the processes that change carbon from one form to another. A carbon budget is needed to fully understand many important issues facing coastal waters. We constructed the carbon budget for coastal waters of eastern North America. We found that about 60% of the carbon entering the domain is from rivers and about 40% is from the atmosphere, while about 80% of the carbon leaving the domain goes to the open ocean and about 20% is buried. Transfers of carbon from wetlands to estuaries and from estuaries to the ocean were as important as transfers of carbon at the domain boundaries. Tidal wetlands and estuaries were found to be important to the carbon budget despite making up only 2.4 and 8.9% of the study domain area, respectively. This study shows that coastal carbon budgets should explicitly consider tidal wetlands, estuaries, shelf waters, and the linkages between them; ignoring any of them may produce a biased picture of coastal carbon cycling.
Key Points
Tidal wetlands, estuaries, and shelf waters each contribute substantially to the carbon budget of eastern North American coastal waters
Study region net ecosystem production, atmospheric uptake, and burial are 20.2 ± 4.4, 5.1 ± 2.4, and 2.5 ± 0.7 Tg C yr−1, respectively
Net lateral carbon fluxes between tidal wetlands, estuaries, and shelf waters are large terms in the carbon budget of eastern North American coastal waters
Autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI; OMIM #130900) is a genetic disorder exhibiting severe hardness defects and reduced fracture toughness of dental enamel. While the ...condition is nonsyndromic, it can be associated with other craniofacial anomalies, such as malocclusions and delayed or failed tooth eruption. Truncation mutations in FAM83H (OMIM *611927) are hitherto the sole cause of ADHCAI. With human genetic studies, Fam83h knockout and mutation–knock-in mouse models indicated that FAM83H does not serve a critical physiologic function during enamel formation and suggested a neomorphic mutation mechanism causing ADHCAI. The function of FAM83H remains obscure. FAM83H has been shown to interact with various isoforms of casein kinase 1 (CK1) and keratins and to mediate organization of keratin cytoskeletons and desmosomes. By considering FAM83H a scaffold protein to anchor CK1s, further molecular characterization of the protein could gain insight into its functions. In this study, we characterized 9 kindreds with ADHCAI and identified 3 novel FAM83H truncation mutations: p.His437*, p.Gln459*, and p.Glu610*. Some affected individuals exhibited hypoplastic phenotypes, in addition to the characteristic hypocalcification enamel defects, which have never been well documented. Failed eruption of canines or second molars in affected persons was observed in 4 of the families. The p.Glu610* mutation was located in a gap area (amino acids 470 to 625) within the zone of previously reported pathogenic variants (amino acids 287 to 694). In vitro pull-down studies with overexpressed FAM83H proteins in HEK293 cells demonstrated an interaction between FAM83H and SEC16A, a protein component of the COP II complex at endoplasmic reticulum exit sites. The interaction was mediated by the middle part (amino acids 287 to 657) of mouse FAM83H protein. Results of this study significantly extended the phenotypic and genotypic spectrums of FAM83H-associated ADHCAI and suggested a role for FAM83H in endoplasmic reticulum–to–Golgi vesicle trafficking and protein secretion (dbGaP phs001491.v1.p1).
Abstract
Spin-valley locking in monolayer transition metal dichalcogenides has attracted enormous interest, since it offers potential for valleytronic and optoelectronic applications. Such an exotic ...electronic state has sparsely been seen in bulk materials. Here, we report spin-valley locking in a Dirac semimetal BaMnSb
2
. This is revealed by comprehensive studies using first principles calculations, tight-binding and effective model analyses, angle-resolved photoemission spectroscopy measurements. Moreover, this material also exhibits a stacked quantum Hall effect (QHE). The spin-valley degeneracy extracted from the QHE is close to 2. This result, together with the Landau level spin splitting, further confirms the spin-valley locking picture. In the extreme quantum limit, we also observed a plateau in the
z
-axis resistance, suggestive of a two-dimensional chiral surface state present in the quantum Hall state. These findings establish BaMnSb
2
as a rare platform for exploring coupled spin and valley physics in bulk single crystals and accessing 3D interacting topological states.
Background and purpose
The pharmacologic effects of pioglitazone on the incidence of Parkinson disease (PD) are not clear. No study has examined the interaction between pioglitazone and statin ...treatment on prevention of PD. This study analyzed the associations between pioglitazone, statins, and the incidence of PD in patients with diabetes mellitus (DM) in Taiwan.
Methods
We used the National Health Insurance database from 1996 to 2013. DM and PD were diagnosed according to the International Classification of Diseases, Ninth Revision, Clinical Modification codes. We used the propensity score‐matching method to match the study groups. Cox regression analyses were employed to calculate the relative risk of the incidence of PD.
Results
There were 48 828 patients matched and categorized equally into the pioglitazone group and the non‐pioglitazone group. The number of PD patients in the pioglitazone group and the non‐pioglitazone group was 275 (1.1%) and 417 (1.7%), respectively. The pioglitazone group had a lower incidence of PD, with an adjusted hazard ratio (aHR) of 0.66 95% confidence interval (CI): 0.57–0.78, and this benefit was dose‐dependent. Of note, as compared with either pioglitazone or statin treatment, our results first showed that the combination of pioglitazone and statins further lowered the risk of PD, with an aHR of 0.78 (95% CI: 0.64–0.94; P = 0.010).
Conclusions
Our study results suggested that pioglitazone could be a promising agent for reducing the incidence of PD in patients with DM, and works synergistically with statins.
Pioglitazone and statins may lower the indidence of Parkinsion disease independently and synergistically in patients with diabetes mellitus.
Background
Liver resection is effective for hepatocellular carcinoma (HCC) exceeding the Milan criteria in selected patients. However, the benefit of anatomical resection (AR) versus non‐anatomical ...resection (NAR) has not been clarified in this patient subgroup. This study aimed to compare outcomes between AR and NAR for HCC exceeding the Milan criteria.
Methods
Data on consecutive patients with HCC exceeding the Milan criteria who underwent liver resection with curative intent over a recent 6‐year interval were extracted from a prospective single‐centre HCC database and examined retrospectively. The postoperative outcomes of patients were compared before and after propensity score matching.
Results
Some 546 patients were included: 264 in the AR and 282 in the NAR group. In the original cohort, the AR group contained more patients with larger tumours, multiple tumours, macroscopic portal vein tumour thrombi, incomplete tumour capsules and microscopic vascular invasion. After propensity score matching, 177 pairs of patients were selected. The baseline data, including liver function and tumour burden, were similar in the matched groups. The 3‐year recurrence‐free survival rate was comparable between the matched NAR and AR groups (36·5 versus 28·5 per cent; P = 0·448). Similar results were observed for 3‐year overall survival (57·5 versus 50·3 per cent; P = 0·385), recurrence patterns and early recurrence rates (57·6 per cent versus 59·9 per cent; P = 0·712).
Conclusion
AR and NAR achieved favourable and similar outcomes for HCC exceeding the Milan criteria in selected patients.
No difference
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