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Background Hepatocellular carcinoma (HCC) is closely associated with chronic liver diseases, particularly liver cirrhosis, which has an altered extracellular matrix (ECM) composition. The influence and its mechanism of the cirrhotic-ECM on the response of HCC to immune checkpoint inhibitor (ICI) remains less clarified.Methods In silico, proteomic and IHC assessment of alteration of cirrhotic-ECM were applied in clinical cohort. Multiple pre-clinical models with ECM manipulation were used to evaluate cirrhotic-ECM’s effect on ICI treatment. In silico, flow cytometry and IHC were applied to explore how cirrhotic-ECM affect HCC microenvironment. In vitro and in vivo experiments were carried out to identify the mechanism of how cirrhotic-ECM undermined ICI treatment.Results We defined “a pro-tumor cirrhotic-ECM” which was featured as the up-regulation of Col1. Cirrhotic-ECM/Col1 was closely related to impaired T cell function and limited aPD-1 response of HCC patients from the TCGA pan cancer cohort and the authors’ institution, as well as in multiple pre-clinical models. Mechanically, cirrhotic-ECM/Col1 orchestrated an immunosuppressive microenvironment (TME) by triggering Col1-DDR1-NFκB-CXCL8 axis, which initiated neutrophil extracellular traps (NETs) formation to shield HCC cells from attacking T cells and impede approaching T cells. Nilotinib, an inhibitor of DDR1, reversed the neutrophils/NETs dominant TME and efficiently enhanced the response of HCC to aPD-1.Conclusions cirrhotic-ECM modulated a NETs enriched TME in HCC, produced an immune suppressive TME and weakened ICI efficiency. Col1 receptor DDR1 could be a potential target synergically used with ICI to overcome ECM mediated ICI resistance. These provide a mechanical insight and novel strategy to overcome the ICI resistance of HCC.

We derive an exact relation for density fluctuations in statistically stationary compressible turbulence. In weakly compressible turbulence, the relation identifies two contributions, corresponding to the acoustic mode and the pseudo-sound mode, respectively, to the density power spectrum, providing a unifying picture for the origin of density fluctuations in turbulent flows with Mach number ≲ 1. Using numerical simulations of driven turbulence, we verified the validity of the exact relations, and examined the contributions of the acoustic and pseudo-sound terms as a function of the Mach number. For simulations of supersonic turbulence, the exact relations provide a tool to quantify the artificial reduction of the density variance by numerical viscosity. The artificial suppression of density fluctuations increases with increasing Mach number, due to the necessity of applying larger numerical diffusion to stabilize stronger shocks. The exact relation also helps to theoretically establish the relation between the density variance and the density-weighted Mach number, $\langle \delta \rho ^2 \rangle /\bar{\rho }^2 = b^2 \mathcal {M}_{\rho }^2$, in supersonic turbulence, which is of crucial importance for the modelling of star formation. Combining with simulations of supersonic turbulence with solenoidal driving and removing the artificial suppression of density fluctuations by numerical viscosity, our exact relation gives an estimate of b ≃ 0.4 for the b parameter.

Nonalcoholic fatty liver disease (NAFLD) can lead to hepatocellular carcinoma (HCC). The level of the transcription factor SOX2 correlates with HCC progression, but its role in fat accumulation remains unclear. Here, a high-fat diet, with and without fructose, significantly upregulated SOX2 in murine liver tissue. Treatment with free fatty acids (FFAs) and fructose upregulated SOX2 in murine FL83B hepatocytes. SOX2 overexpression or knockdown regulated triglyceride synthesis and lipid accumulation after FFA stimulation. CD36, a fatty acid transporter, and Yes-associated protein (YAP), a downstream molecule of the Hippo signaling pathway, were upregulated by FFA/fructose in vivo and in vitro. Transcriptional regulation of CD36 by SOX2 suggested the involvement of CD36 in SOX2-mediated hepatic steatosis. Thus, SOX2 may be a target to prevent NAFLD development.

Secreted frizzled-related protein 5 (SFRP5) plays a pivotal role in regulating the development of many tissues and organs, however, as an inhibitor of Wnt signaling, the role of SFRP5 in vitiligo remains unknown. Hence, we speculated that SFRP5 might be associated with melanogenesis in melanocytes by regulating Wnt signaling in vitiligo. In this study, we found that SFRP5 was overexpressed in the skin lesions of patients with vitiligo. Compared with that in normal epidermal melanocytes (PIG1), the expression of SFRP5 was increased in vitiligo melanocytes (PIG3V). To investigate the effect of SFRP5 on melanin synthesis, PIG1 cells were infected with recombinant SFRP5 adenovirus (AdSFRP5), and PIG3V cells were infected with recombinant siSFRP5 adenovirus (AdsiSFRP5). The results showed that SFRP5 overexpression inhibited melanin synthesis in PIG1 cells through downregulation of microphthalmia-associated transcription factor (MITF) and its target proteins via suppression of the Wnt/β-catenin signaling pathway. Accordingly, SFRP5 silencing increased melanin synthesis and activated the Wnt signaling pathway in PIG3V cells. Moreover, SFRP5 overexpression also downregulated the transcriptional activity of T cell factor/lymphoid enhancer factor (TCF/LEF) in PIG1 cells. Furthermore, this inhibitory effect of SFRP5 on melanin synthesis was reversed by treatment with the β-catenin agonist, SKL2001. The inhibitory action of SFRP5 in pigmentation was further confirmed in vivo using a nude mouse model. Hence, our results indicate that SFRP5 can inhibit melanogenesis in melanocytes. Additionally, our findings showed that SFRP5 plays a vital role in the development of vitiligo, and thus may serve as a potential therapeutic target for vitiligo.

The fast blue optical transients (FBOTs) are a new population of extragalactic transients of unclear physical origin. A variety of mechanisms have been proposed including failed supernova explosion, shock interaction with a dense medium, young magnetar, accretion onto a compact object, and stellar tidal disruption event, but none is conclusive. Here we report the discovery of a possible X-ray quasi-periodicity signal with a period of $\sim$250 second (at a significance level of 99.76%) in the brightest FBOT AT2018cow through the analysis of XMM-Newton/PN data. The signal is independently detected at the same frequency in the average power density spectrum from data taken from the Swift telescope, with observations covering from 6 to 37 days after the optical discovery, though the significance level is lower (94.26%). This suggests that the QPO frequency may be stable over at least 1.1$\times$ 10$^{4}$ cycles. Assuming the $\sim$250 second QPO to be a scaled-down analogue of that typically seen in stellar mass black holes, a black hole mass of $\sim10^{3}-10^{5}$ solar masses could be inferred. The overall X-ray luminosity evolution could be modeled with the stellar tidal disruption by a black hole of $\sim10^4$ solar masses, providing a viable mechanism to produce AT2018cow. Our findings suggest that other bright FBOTs may also harbor intermediate-mass black holes., 18 pages, 10 figures. Accepted for publication in Research in Astronomy and Astrophysics

Fragile X-related protein 1 (FXR1) is an RNA-binding protein that can regulate specific mRNA decay in cells. Our previous study showed that FXR1 expression was significantly decreased in trophoblasts from patients with unexplained recurrent spontaneous abortion (RSA); however, the role of FXR1 in trophoblast function during early placenta development has not been fully elucidated. In this study, we found that knockdown of FXR1 using siRNA effectively inhibited the migration of HTR-8 cells and extravillous trophoblast (EVT) outgrowth in an ex vivo extravillous explant culture model. Furthermore, through analysis of a panel of cytokines, we found that the GDF-15 protein was upregulated after knockdown of FXR1 in HTR-8/SVneo cells. This was further confirmed by western blotting and immunofluorescence in HTR-8/SVneo cells and an extravillous explant. Our data also showed that FXR1 expression was downregulated and GDF-15 was upregulated in chorionic villous tissues from RSA patients compared with those from healthy controls (HCs). Further, immunohistochemistry showed a strong expression of GDF-15 in chorionic villous tissue in the RSA group, which was mainly distributed in villous trophoblasts (CTBs) and syncytiotrophoblasts (STBs). Moreover, knockdown of GDF-15 enhanced the migration of HTR-8 cells, while overexpression of GDF-15 using plasmid or treatment with recombinant human GDF-15 protein inhibited trophoblast migration. Importantly, RNA-binding protein immunoprecipitation showed that FXR1 directly bound to the 3′-UTR of GDF-15 mRNA to promote GDF-15 mRNA decay. Together, our data provide new insight into the function of FXR1 in human placenta via regulation of GDF-15 expression in trophoblasts and suggest a possible pathological process involved in RSA.

The advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic options of hepatobiliary malignancies. However, the clinical benefit provided by immunotherapy seems limited to a small subgroup of patients with hepatobiliary malignancies. The identification of reliable predictors of the response to immunotherapy is urgently needed.Literature search was conducted in PubMed for relevant articles published up to May 2022. Information of clinical trials was obtained from https://clinicaltrials.gov/.Biomarkers for ICI response of hepatobiliary malignancies remain in the exploration stage and lack compelling evidence. Tumor programmed death-ligand 1 (PD-L1) expression is the most widely studied biomarker in hepatocellular carcinoma (HCC) and biliary tract cancers (BTCs), but there are conflicting results on its predictive potential. Tumor mutational burden (TMB) is generally low both in HCC and BTCs, and the clinical trials of TMB are rare in hepatobiliary malignancies. Promisingly, mismatch repair deficiency (dMMR)/high microsatellite instability (MSI-H) may be a predictive biomarker of response to anti-PD-1 therapy in BTCs. Furthermore, some emerging biomarkers, such as gut microbiota, show predictive potential in the preliminary studies. Radiomics and liquid-biopsy biomarkers, including circulating tumor cells, circulating tumor DNA (ctDNA) and exosomal PD-L1 provide a quick and non-invasive approach for monitoring the ICI response, showing a new promising direction.Multiple potential biomarkers for predicting ICI response of hepatobiliary malignancies have been explored and tried to apply in clinic. Yet there is no robust evidence to prove their clinical value in predicting immunotherapeutic response for patients with hepatobiliary malignancies. The identification of predictors for response to ICIs is an urgent need and major challenge. Further studies are warranted to validate the role of emerging biomarkers in predicting immunotherapeutic responses.

A nuclear magnetic resonance (NMR)-based method was developed to quickly and accurately determine porosities and densities of tight reservoir rocks from drill cuttings. The method combines low-fiel...

Spin relaxation, a defining mechanism of nuclear magnetic resonance (NMR), has been a prime method for determining three-dimensional molecular structures and their dynamics in solution. It also plays key roles for contrast enhancement in magnetic resonance imaging (MRI). In bulk solutions, rapid Brownian molecular diffusion modulates dipolar interactions between a spin pair from different molecules, resulting in very weak intermolecular relaxations. We show that in fluids confined in nanospace or nanopores (nanoconfined fluids) the correlation of dipolar coupling between spin pairs of different molecules is greatly enhanced by the nanopore constraint boundaries on the molecular diffusion, giving rise to an enhanced correlation for the spin pair. As a result, the intermolecular dipolar interaction behaves cooperatively, which leads to a large intermolecular dipolar relaxation rate and opposite in sign to the bulk solution. We found that the classical NMR relaxation theory fails to capture these observations in a nanoconfined fluid environment. Hence, we developed a formal theory and experimentally confirmed that enhanced correlation and cooperated relaxation are ubiquitous in nanoconfined fluids. The newly discovered phenomenon and the developed NMR method reveal new applications in a broad range of synthesized and naturally occurring materials in the field of nanofluidics to study molecular dynamics and structure as well as for MRI image enhancement.

Crosscorrelation is a classical signal-processing technique that plays an important role in exploration and earthquake geophysics. Seismic velocity estimation utilizes the crosscorrelation between observed and predicted seismic records in traveltime tomography. The crosscorrelation between two stations represents the Green’s functions retrieved from ambient noises in passive seismic interferometry. It can be used to estimate the subsurface velocity and amplitude information. The calculation of crosscorrelation usually assumes that the input data are stationary; however, the real seismic data are often non-stationary, due to the presence of multiple wave-modes and background noises. The seismic crosscorrelations often have low signal-to-noise ratio and frequently fail to provide correct information for subsequent processing. To address this problem, we develop a comprehensive technique to reduce contamination and improve the quality of crosscorrelation in the wavelet domain. The new procedure includes the forward wavelet transformation of raw records, the crosscorrelation between wavelet coefficients, single-channel image object detection, multi-channel Kalman-filter object tracking, and inverse wavelet transformation to produce the new crosscorrelation gathers. We effectively remove the unwanted components associated with contaminated wave-modes as the proposed detection and tracking algorithm can accurately extract the target wave-mode. We validate the method for three datasets: a marine streamer survey, a borehole survey, and a broadband dataset from seismology stations. We demonstrate that the proposed method can significantly improve the signal-to-noise ratio of the seismic crosscorrelations, considerably enhancing the quality of the data for subsequent advanced crosscorrelation-based seismic processing.

Background. Soil contamination by hexavalent chromium is becoming a main environmental concern in China. This study developed a sewage sludge biochar modified by FeSO4 (CHBC) as a new reductant for Cr(VI)-contaminated soil. The effectiveness of CHBC-stabilized Cr(VI)-contaminated soil was investigated. Methods. Typical industrial Cr(VI)-contaminated soil in China was chosen as the medium. The total and Cr(VI) contents of the contaminated soil were 1014.6 and 973.5 mg/kg, respectively. The effectiveness of the Cr(VI)-contaminated soil stabilized by CHBC was investigated by the leaching test (US EPA method 1312), the simplified bioaccessibility extraction test (US EPA 2007 protocol and British Geological Survey), alkaline digestion (US EPA method 3060A), sequential extraction (BCR sequential extraction procedure), X-ray diffraction, and the risk assessment code test. Results. Results show that CHBC substantially reduced the leachability and Cr(VI) content of the contaminated soil. The leachability and content of Cr(VI) were lower than the thresholds of the Environmental Quality Standards of Soil in China for civil reuse and the China Environmental Quality Standards of surface water for civil use when the soil was stabilized with 10% dosage of CHBC. Conclusion. CHBC is highly efficient in stabilizing Cr(VI) and can effectively reduce the leachability and bioavailability of Cr in contaminated soil and thus feasible for stabilizing Cr(VI)-contaminated soil and shows potential for application in the field.

The thermogenic transformation of kerogen into hydrocarbons accompanies the development of a pore network within the kerogen that serves as gas storage locations both in pore space and the surface ...

During bone formation, mesenchymal progenitor cells mature into bone-forming osteoblasts after undergoing several stages of differentiation. Impaired bone formation is a predominant finding in glucocorticoid (GC)-induced osteoporosis (GIO). Osteoblasts at different stages of maturation can be affected by excessive endogenous or therapeutic GCs. Sex-determining region Y-box 2 (SOX2) is normally expressed in immature osteoblasts, but its overexpression can suppress osteoblast differentiation. This study aimed to evaluate whether GC affects SOX2 expression in osteoblasts, and whether SOX2 contributes to GC-induced inhibition of osteoblast differentiation. Treatment with GCs such as dexamethasone (Dex) or hydrocortisone enhanced SOX2 expression. Silencing SOX2 improved inhibition of GC-induced osteoblast differentiation, whereas SOX2 overexpression decreased mineralized nodule formation and RUNX2 and Osterix expression in MC3T3-E1 cells. On the contrary, when C3H10T1/2 uncommitted mesenchymal stem cells were subjected to SOX2 overexpression, RUNX2 expression increased. As a mechanism of Dex-induced SOX2 upregulation in preosteoblasts, we found that the STAT3 pathway or GC receptor (GR) is involved, using a GR antagonist, STAT3 regulators, and chromatin immunoprecipitation assays. Moreover, mice treated with Dex for 4 weeks showed a notable increase in SOX2 expression in the bones and an increased ratio of procollagen type 1 N-terminal propeptide to osteocalcin in the plasma than in control mice. This study demonstrated that GC enhances SOX2 expression in vitro in osteoblast and in vivo in the mice bone, which affects bone-forming activity differently depending on the differentiation stage of osteoblast-lineage cells. Our results provide new insights into prevention and treatment against impaired bone formation in GIO.

Permeability is a fundamentally important property of reservoir rocks that governs the flow of the reservoir fluids and production rates. Many methods have been developed to estimate permeability, including well established and documented laboratory measurements on whole core and plugs, analysis of formation test data, and analysis of production. Obtaining permeability from nuclear magnetic resonance (NMR) T1 or T2 has proven to be a cost effective method that can provide continuous permeability along a wellbore. This method uses a transform function on NMR well log data to calculate permeability. An accurate NMR permeability transform requires calibration to fit local data of a specific field based on measured data from representative cores from the field. The general form of the permeability transform developed for conventional sandstone and carbonate reservoirs does not work well for extremely tight reservoirs such as source rocks. Here we show a generic optimization method to find the optimal permeability transform for any tight reservoirs using NMR log data and laboratory measured permeability data from samples at selected depth of the logged well. This optimization method is applied to a source rock well and a permeability transform was obtained. The transform is a function of the movable fluid in the rock and logarithm mean of the NMR relaxation time. The permeability calculated from the transform is comparable to measured permeability from core samples.

BackgroundTertiary lymphoid structures (TLSs) have been proposed to assess the prognosis of patients with cancer. Here, we investigated the prognostic value and relevant mechanisms of TLSs in colorectal cancer liver metastases (CRCLM).Methods603 patients with CRCLM treated by surgical resection from three cancer centers were included. The TLSs were categorized according to their anatomic subregions and quantified, and a TLS scoring system was established for intratumor region (T score) and peritumor region (P score). Differences in relapse-free survival (RFS) and overall survival (OS) between groups were determined. Multiplex immunohistochemical staining (mIHC) was used to determine the cellular composition of TLSs in 40 CRCLM patients.ResultsT score positively correlated with superior prognosis, while P score negatively associated with poor survival (all p=0.029, p=0.047 and p=0.041, respectively), and the frequencies of Treg cells and M2 macrophages were positively correlated with P score, while the frequencies of Tfh cells were positively associated with T scores in intratumor TLSs (all pConclusionsThe distribution and abundance of TLSs is significantly associated with RFS and OS of CRCLM patients, and a novel immune class was proposed for predicting the prognosis of CRCLM patients.

During the inspiralling of a white dwarf (WD) into an intermediate-mass black hole (~ 10^{2-5} M_sun), both gravitational waves (GWs) and electromagnetic (EM) radiation are emitted. Once the eccentric orbit's pericenter radius approaches the tidal radius, the WD would be tidally stripped upon each pericenter passage. The accretion of these stripped mass would produce EM radiation. It is suspected that the recently discovered new types of transients, namely the quasi-periodic eruptions and the fast ultraluminous X-ray bursts, might originate from such systems. Modeling these flares requires a prediction of the amount of stripped mass from the WD and the details of the mass supply to the accretion disk. We run hydrodynamical simulations to study the orbital parameter dependence of the stripped mass. We find that our results match the analytical estimate that the stripped mass is proportional to z^{5/2}, where z is the excess depth by which the WD overfills its instantaneous Roche lobe at the pericenter. The corresponding fallback rate of the stripped mass is calculated, which may be useful in interpreting the individual flaring light curve in candidate EM sources. We further calculate the long-term mass-loss evolution of a WD during its inspiral and the detectability of the GW and EM signals. The EM signal from the mass-loss stage can be easily detected: the limiting distance is ~ 320(M_h/10^4 M_sun) Mpc for Einstein Probe. The GW signal, for the space-borne detectors such as Laser Interferometer Space Antenna or TianQin, can be detected only within the Local Supercluster (~ 33 Mpc)., Comment: 18 pages, 13 figures, Accepted for publication in ApJ

Aberrant activation of receptor tyrosine kinases (RTKs) and the subsequent metabolic reprogramming play critical roles in cancer progression. Our previous study has shown that Golgi membrane protein 1 (GOLM1) promotes hepatocellular carcinoma (HCC) metastasis by enhancing the recycling of RTKs. However, how this RTK recycling process is regulated and coupled with RTK degradation remains poorly defined. Here, we demonstrate that cholesterol suppresses the autophagic degradation of RTKs in a GOLM1-dependent manner. Further mechanistic studies reveal that GOLM1 mediates the selective autophagy of RTKs by interacting with LC3 through an LC3-interacting region (LIR), which is regulated by a cholesterol-mTORC1 axis. Lowering cholesterol by statins improves the efficacy of multiple tyrosine kinase inhibitors (TKIs) in vivo. Our findings indicate that cholesterol serves as a signal to switch GOLM1-RTK degradation to GOLM1-RTK recycling and suggest that lowering cholesterol by statin may be a promising combination strategy to improve the TKI efficiency in HCC.

A novel photoredox-catalyzed radical addition of methylene-2-oxazolines has been developed under visible light irradiation to synthesize monofluorooxazoles with a quaternary carbon center using 2-bromo-2-fluoro-3-oxo-3-phenylpropionates as radical source. This method with a simple protocol, scalability and high yield offers a facile path to get diverse monofluorinated oxazoles with quaternary C-F centers, which are a class of highly valuable motifs and synthons.

Organic-rich shales have pore size on nanometer scale and permeability on the order of nano-Darcy. These properties give rise to significant challenges in understanding and modeling flow processes during the hydrocarbon production from shale reservoirs. During production, light hydrocarbons move from nanopores in the rock matrix to fractures generated by hydraulic fracturing to the well. Diffusion becomes a key mechanism in controlling hydrocarbon transport within matrix and from matrix to fractures. However, reliable experimental data for hydrocarbon diffusion coefficients in organic-rich shales are still lacking in the literature. This study presents experimental measurements of in situ methane diffusion coefficients in shales using a pulse-field-gradient nuclear magnetic resonance method. This method measures the diffusion coefficient at equilibrium state and thus eliminates the possibility of fluid flow effects in laboratory measurement generated from pressure or concentration gradient. The measured methane diffusion coefficients in shales are two orders of magnitude smaller than those in the bulk state in the pressure range from 75 to 6000 psi. The measured data can be used to more accurately evaluate and model the production from shale reservoirs.