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Acetylcholine (ACh) is an important neuromodulator in various cognitive functions. However, it is unclear how ACh influences neural circuit dynamics by altering cellular properties. Here, we investigated how ACh influences reverberatory activity in cultured neuronal networks. We found that ACh suppressed the occurrence of evoked reverberation at low to moderate doses, but to a much lesser extent at high doses. Moreover, high doses of ACh caused a longer duration of evoked reverberation, and a higher occurrence of spontaneous activity. With whole-cell recording from single neurons, we found that ACh inhibited excitatory postsynaptic currents (EPSCs) while elevating neuronal firing in a dose-dependent manner. Furthermore, all ACh-induced cellular and network changes were blocked by muscarinic, but not nicotinic receptor antagonists. With computational modeling, we found that simulated changes in EPSCs and the excitability of single cells mimicking the effects of ACh indeed modulated the evoked network reverberation similar to experimental observations. Thus, ACh modulates network dynamics in a biphasic fashion, probably by inhibiting excitatory synaptic transmission and facilitating neuronal excitability through muscarinic signaling pathways.

We study the sensor layouts of surface monitoring systems for injection areas in hydraulic fracturing experiments, which maximize the accuracy of retrieved moment tensors. The moment tensors (MTs) are determined using noisy synthetic P-wave amplitudes of microearthquakes with varying mechanisms. An optimum sensor layout is searched by minimizing a difference between the true and inverted MTs. First, we tested the efficiency of the circular networks. We focused on one-circle and two-circle layouts of various sizes and numbers of sensors on each circle and with their centre in the epicentral region. The results show that the optimal layout for events distributed within a circular epicentral area is characterized by: (1) one sensor fixed in the centre of the area; (2) about 1/10 of the total number of sensors gathered near the centre; and (3) the rest of sensors evenly distributed on a circle surrounding the area with the take-off angle of 135°. In homogeneous media, this angle corresponds to the radius of the circle comparable with depth of microearthquakes. Second, we compared the efficiency of the circular layout with other layouts: regular-grid, star-shaped and uniform focal-sphere layouts. Taking 25 sensors and 81 sensors as examples, we show that the two-circle layout is always the best, which means that we can achieve more accurate MTs using the circular layout than with other layouts, if the number of sensors in the experiment is fixed. This contradicts a common opinion that networks, which cover the target area, work equally well irrespective of their layout.

GSK3β interacting protein (GSKIP) is a small A-kinase anchor protein previously reported to mediate the N-cadherin/β-catenin pool for differentiation in SH-SY5Y cells through overexpression of GSKIP to present the neuron outgrowth phenotype. To further investigate how GSKIP functions in neurons, CRISPR/Cas9 technology was utilized to knock out GSKIP (GSKIP-KO) in SH-SY5Y. Several GSKIP-KO clones resulted in an aggregation phenotype and reduced cell growth without retinoic acid (RA) treatment. However, neuron outgrowth was still observed in GSKIP-KO clones treated with RA. The GSKIP-KO clones exhibited an aggregation phenotype through suppression of GSK3β/β-catenin pathways and cell cycle progression rather than cell differentiation. Gene set enrichment analysis indicated that GSKIP-KO was related to epithelial mesenchymal transition/mesenchymal epithelial transition (EMT/MET) and Wnt/β-catenin/cadherin signaling pathways, suppressing cell migration and tumorigenesis through the inhibition of Wnt/β-catenin mediated EMT/MET. Conversely, reintroduction of GSKIP into GSKIP-KO clones restored cell migration and tumorigenesis. Notably, phosphor-β-catenin (S675) and β-catenin (S552) but not phosphor-β-catenin (S33/S37/T41) translocated into the nucleus for further gene activation. Collectively, these results suggested that GSKIP may function as an oncogene to form an aggregation phenotype for cell survival in harsh environments through EMT/MET rather than differentiation in the GSKIP-KO of SH-SY5Y cells. Graphical abstract

Acetone is a solvent used in many laboratories and factories. Serious problems will occur when it is exposed to the environment. Therefore, a new design hydrophobicity bimetallic metal material (10-Fe1Mn1-USY) was prepared for acetone adsorption under conditions of high humidity. Hydrophobic Y type zeolite was used to prepare bimetallic metal materials and the effect of different operating parameters (including different material, humidity, temperature, pollutant concentration, residence time, and regeneration) on the efficiency of acetone treatment was examined. Isothermal adsorption model, kinetics and thermodynamic model analysis were also used to establish the reaction mechanism. The 10-Fe1Mn1-USY material has good adsorption capacity (133 mg g−1) for acetone under a relative humidity of 50%. The main factors affecting the adsorption capacity are the contact angle, hydrophobicity, specific surface area, and Si/Al of the material. The isothermal adsorption and the kinetic adsorption behavior of 10-Fe1Mn1-USY material for acetone are more suitable for the Temkin isotherm adsorption model and the pseudo-first-order kinetic model. The adsorption of acetone by 10-Fe1Mn1-USY material is dominated by intra-particle diffusion. According to the thermodynamic analysis results, the adsorption behavior of 10-Fe1Mn1-USY material for acetone is a type of physical adsorption, and a spontaneous and non-sequential reaction.

The coronavirus disease 2019 (COVID-19) pandemic has caused an unprecedented disruption to health care systems around the globe. Stroke is still an ongoing issue during the pandemic. We investigated the impact of the COVID-19 outbreak on emergent stroke care in Beijing, China. This is a retrospective analysis of two groups of patients with acute ischaemic stroke (AIS) registered in the Beijing Emergency Care Database between January 1, 2019, and December 31, 2020. Based on a database including 77 stroke centres, the quantity and quality of emergency care for stroke were compared. Subgroup analyses based on hospitals in different areas (high-risk and low/medium-risk areas) were carried out. A total of 6440 and 8699 admissions with suspected stroke were recorded in 2020 and 2019, respectively. There were no significant differences in the mean age and sex distribution for the patients between the two observational periods. The number of AIS admissions decreased by approximately 23.9% during the COVID-19 pandemic compared to that during the prepandemic period. The proportions of intravenous thrombolysis and endovascular treatment were 76.4% and 13.1%, respectively, in 2020, which were higher than those in 2019 (71.7% and 9.3%, respectively). There was no statistically significant difference in the time from stroke onset to arrival at the hospital (97.97 ± 23.09 min vs. 99.40 ± 20.76 min, p = 0.832) between the two periods. The door-to-needle time for thrombolysis (44.92 ± 9.20 min vs. 42.37 ± 9.06 min, p p

In the presence of an MMC-HVDC system, current differential protection (CDP) has the risk of failure in operation under an internal fault. In addition, CDP may also incur security issues in the presence of current transformer (CT) saturation and outliers. In this paper, a current trajectory image-based protection algorithm is proposed for AC lines connected to MMC-HVDC stations using a convolution neural network improved by a channel attention mechanism (CA-CNN). Taking the dual differential currents as two-dimensional coordinates of the moving point, the moving-point trajectories formed by differential currents have significant differences under internal and external faults. Therefore, internal faults can be identified using image recognition based on CA-CNN. This is improved by a channel attention mechanism, data augmentation, and adaptive learning rate. In comparison with other machine learning algorithms, the feature extraction ability and accuracy of CA-CNN are greatly improved. Various fault conditions like different network structures, operation modes, fault resistances, outliers, and current transformer saturation, are fully considered to verify the superiority of the proposed protection algorithm. The results confirm that the proposed current trajectory image-based protection algorithm has strong learning and generalizability, and can identify internal faults reliably.

The mutation of ClZISO identified in EMS-induced watermelon leads to photosensitive flesh in watermelon. Watermelon (Citrullus lanatus) has a colorful flesh that attracts consumers and benefits human health. We developed an ethyl-methanesulfonate mutation library in red-fleshed line '302' to create new flesh color lines and found a yellow-fleshed mutant which accumulated ζ-carotene. The initial yellow color of this mutant can be photobleached within 10 min under intense sunlight. A long-term light-emitting diode (LED) light treatment turned flesh color from yellow to pink. We identified this unique variation as photosensitive flesh mutant ('psf'). Using bulked segregant analysis, we fine-mapped an EMS-induced G-A transversion in 'psf' which leads to a premature stop codon in 15-cis-ζ-carotene isomerase (ClZISO) gene. We detected that wild-type ClZISO is expressed in chromoplasts to catalyze the conversion of 9,15,9'-tri-cis-ζ-carotene to 9,9'-di-cis-ζ-carotene. The truncated ClZISO

Industrial agglomeration (IA) has greatly promoted the improvement of industrial efficiency (IE), but it has also brought serious environmental pollution (EP), which in turn affects sustainable industrial development. Therefore, this study built a theoretical derivation model including pollution output and used a vector error correction model (VECM) and three-stage simultaneous equations (3SLS) to explore the mechanisms among IA, EP and sustainable IE. The following conclusions were reached: (1) The relationship between IA and EP presents an inverted U-shape and is located on the left side of the inverted U-shape curve. IA has increased emissions of industrial sulphur dioxide, industrial soot and industrial wastewater pollutants, but is conducive to IE. Increased EP will inhibit both IA and the level of IE. (2) Both IA and low EP can enhance the level of sustainable IE. (3) IE plays a mitigating role in IA and EP; it will weaken the inhibitory effect of EP on IA and strengthen the impact of IA on EP. In the future, China should continue its industrialization process to promote the scale of IA and strictly control the discharge of industrial pollutants to reduce EP. Simultaneously, the government should encourage industrial enterprises to improve technological innovation to promote IE. IA, EP and IE form a virtuous circle that promotes the development of the industrial economy and optimizes the environment. This approach can also be applied to other regions to provide decision support for the sustainable development of industry.

Motivated by the parameter identification problem of a reaction-diffusion transport model in a vapor phase infiltration processes, we propose a Bayesian optimization procedure for solving the inverse problem that aims to find an input setting that achieves a desired functional output. The proposed algorithm improves over the standard single-objective Bayesian optimization by (i) utilizing the generalized chi-square distribution as a more appropriate predictive distribution for the squared distance objective function in the inverse problems, and (ii) applying functional principal component analysis to reduce the dimensionality of the functional response data, which allows for efficient approximation of the predictive distribution and the subsequent computation of the expected improvement acquisition function.

The relationship between microstructure and corrosion behavior of high-grade pipeline steel under low-temperature conditions was comparatively investigated by the potentiodynamic polarization and electrochemical impedance spectroscopy test combining with optical micrographs, scanning electron microscopy, transmission electron microscopy and electron back-scattered diffraction. The results showed that, compared with room and high temperature, low temperature could influence the corrosion behavior of high-grade pipeline steel, which means that the corrosion potential and current density decreased and the corrosion resistance increased significantly. Moreover, double layer structures of the interface became thicker and more compact. Under low-temperature environment, acicular ferrite had the martensite/austenite constituents with less amount and smaller size, a higher density of low angle grain boundaries and smaller effective grain sizes compared with granular bainite, which demonstrated higher corrosion resistance.

For past two decades, p53 has been claimed as the primary sensor initiating apoptosis. Under severe cellular stress, p53 transcriptional activity activates BH3-only proteins such as Bim, Puma, or Noxa to nullify the inhibitory effects of anti-apoptotic proteins on pro-apoptotic proteins for mitochondrial outer membrane permeabilization. Cellular stress determines the expression level of p53, and the amount of p53 corresponds to the magnitude of apoptosis. However, our studies indicated that Bim and Puma are not the target genes of p53 in three cancer models, prostate cancer, glioblastoma, and osteosarcoma. Bim counteracted with Bcl-xl to activate apoptosis independently of p53 in response to doxorubicin-induced severe DNA damage in prostate cancer. Moreover, the transcriptional activity of p53 was more related to cell cycle arrest other than apoptosis for responding to DNA damage stress generated by doxorubicin in prostate cancer and glioblastoma. A proteasome inhibitor that causes protein turnover dysfunction, bortezomib, produced apoptosis in a p53-independent manner in glioblastoma and osteosarcoma. p53 in terms of both protein level and nuclear localization in combining doxorubicin with bortezomib treatment was obviously lower than when using DOX alone, inversely correlated with the magnitude of apoptosis in glioblastoma. Using a BH3-mimetic, ABT-263, to treat doxorubicin-sensitive p53-wild type and doxorubicin-resistant p53-null osteosarcoma cells demonstrated only limited apoptotic response. The combination of doxorubicin or bortezomib with ABT-263 generated a synergistic outcome of apoptosis in both p53-wild type and p53-null osteosarcoma cells. Together, this suggested that p53 might have no role in doxorubicin-induced apoptosis in prostate cancer, glioblastoma and osteosarcoma. The effects of ABT-263 in single and combination treatment of osteosarcoma or prostate cancer indicated a dual control to regulate apoptosis in response to severe cellular stress. Whether our findings only apply in these three types of cancers or extend to other cancer types remains to be explored.

Background The safety and effectiveness of lung segmentectomy in patients with early non-small cell lung cancer (NSCLC) remains controversial. We have therefore reviewed the clinicopathologic characteristics and survival outcomes of patients treated with lobectomy or segmentectomy for early T (> 2 and ≤ 3 cm) N0M0 NSCLC. Methods We obtained data from the Surveillance, Epidemiology, and End Results database for patients who underwent lobectomy or segmentectomy between 2004 and 2015. To reduce bias and imbalances between the treatment groups, propensity score matching analysis was performed. We used Kaplan–Meier curves to estimate overall survival (OS) and lung cancer-specific survival (LCSS). We conducted univariate and multivariate Cox proportional hazards regression analyses to identify independent prognostic factors for OS and cancer-specific survival, and applied the Cox proportional hazards model to create forest plots. Results Before matching, both univariate and multivariate Cox regression analyses revealed that patients who underwent lobectomy exhibited better OS (P P = 0.001) than patients who underwent segmentectomy. However, after matching, survival differences between the groups were not significant; OS (P = 0.434) and LCSS (P = 0.593). Regression analyses revealed that age and tumor grade were independent predictors of OS and LCSS (P Conclusions Patients with stage T (> 2 and ≤ 3 cm) N0M0 NSCLC undergoing segmentectomy can obtain OS and LCSS similar to those obtained with lobectomy. Further studies are required considering the solid component effects and pathologic tumor types regarding segmentectomies. Additional long-term survival and outcome analyses should be conducted with larger cohorts.

Pachypleurosaurs (Pachypleurosauroidea) are a group of small to medium-sized, lizard-like marine reptiles in the Early to Middle Triassic, including Pachypleurosauridae, Keichousauridae and closely related taxa. The group is generally considered as a sauropterygian radiation, but its phylogenetic interrelationships remain highly debated. Here, we present a new pachypleurosaurid, Honghesaurus longicaudalis gen. et sp. nov., from the early Middle Triassic (Anisian, ~ 244 Ma) marine deposits in Luxi, Yunnan, China. The discovery documents the first really long-tailed pachypleurosaur with totally 121 (69 caudal) vertebrae, providing new evidence for the vertebral multiplication and ecological adaption of this group. The long trunk associated with an incredibly long tail could provide Honghesaurus the advantage of maneuverability and energy efficiency for lateral undulatory swimming. Honghesaurus, although possessing a series of autapomorphies, fills the morphological gap between Qianxisaurus from the Ladinian Xingyi Biota and Wumengosaurus from the Anisian Panxian Biota. Phylogenetic studies unite these three pachypleurosaurids as a monophyletic clade above European pachypleurosaurid clades and provide new insights into the interrelationships of this group. Our scenario of pachypleurosaurian phylogeny combined with the stratigraphic data imply that the Tethys Ocean was a west–east corridor for dispersal of pachypleurosaurids from Europe into South China.

Microvascular invasion (MVI) is a risk factor for postoperative survival outcomes for hepatocellular carcinoma (HCC) after liver resection (LR). This study aims to investigate the actual long-term survival and its associated prognostic factors after LR for HCC patients with MVI. This study was conducted on HCC patients with MVI who underwent LR from January 2009 to December 2012 at five major hospitals in China. The patients were divided into the ‘long-term survivor group’ and the ‘short-term survivor group’. The clinicopathologic characteristics, perioperative data and survival outcomes were compared between these two groups. Univariate and multivariate regression analyses were performed to identify predictive factors associated with long-term survival outcomes. The study included 1517 patients with an actual 5-year survival rate of 33.3%. Multivariate regression analysis revealed that HBV DNA > 104 IU/mL, alanine aminotransferase > 44 U/L, alpha-fetoprotein > 400 ng/ml, anatomical hepatectomy, varices, intraoperative blood loss > 400 ml, tumor diameter > 5 cm, tumor number, satellite nodules, tumor encapsulation, wide resection margin and adjuvant transarterial chemoembolization (TACE) were independent prognostic factors associated with actual long-term survival. One-third of HCC patients with MVI reached the long-term survival milestone of 5 years after resection. Anatomical hepatectomy, controlling intraoperative blood loss, a wide resection margin, and postoperative adjuvant TACE should be considered for patients to achieve better long-term survival outcomes.

High-dose methotrexate (HDMTX) combined with leucovorin (LV) is the first-line drug therapy for many kinds of malignant tumors. However, the specific treatment plans, such as dosage and duration of administration, are usually formulated according to the clinician’s experience and therapeutic drug monitoring (TDM) of methotrexate in patients’ plasma, which are responsible for strong individual differences of drug usage. A large number of studies have shown that methotrexate targets the inside of the cell. The key cytotoxic component is the methotrexate polyglutamates (MTXPGs) in the cell. The concentration of methotrexate in plasma does not reflect the efficacy and side effects well. Based on mass spectrometry technology, we developed and validated an accurate, sensitive, and stable method to quantify the intracellular MTX (MTXPG1) and its metabolites MTXPG2–7 simultaneously. The lower limit of quantification was 0.100 ng/ml, and the run time was only 3 min. Moreover, our team has already developed two LC-MS/MS-based methods to respectively quantify methotrexate in plasma samples and two key proteins (γ-glutamyl hydrolase [GGH] and folylpolyglutamate synthetase [FPGS]) in peripheral blood mononuclear cells (PBMC). Through these highly sensitive and accurate approaches, we have gained a deep understanding of the whole pharmacokinetic process of MTX and explored the key factors affecting the accumulation process of intracellular active components (MTXPGs). Based on this research, it is possible to find a more effective way to provide an accurate reference for clinical drug use than traditional therapeutic drug monitoring (TDM).

Gadolinium (Gd)-contrast MRI for reliable detection of blood–brain barrier (BBB) breakdown is widely used in neuromyelitis optica spectrum disorder (NMOSD) attack. Nonetheless, little is known about the predictive role of gadolinium-enhancing lesion in prognosis of NMOSD attack. The aim of this work is to investigate the predictive value of persistently Gd-enhanced lesions to medium-term outcome after attack. Data for this analysis came from an ongoing prospective cohort study (CLUE). NMOSD patients with acute attack were enrolled from January 2019 to March 2020. All patients underwent Gd-contrast MRI at baseline and 1 month, and disability was assessed by Expanded Disability Status Scale (EDSS). Primary outcome was EDSS improvement from baseline to month 6. Multiple logistic regression identified predictors for poor recovery of NMOSD attack. Forty-one participants were analyzed, of which 21 patients had persistently Gd-enhancing lesions. Patients in no enhancement (NE) group showed a significant shift in 6-month EDSS distributions compared with those in persistent enhancement (PE) group (p = 0.005). Poor recovery rate of the PE group was higher than that of the NE group at 6 months (p = 0.033). In patients with aquaporin-4-positive, first-attack, transverse myelitis or in a high-dose steroid treatment subgroup, the improvement of EDSS scores in the PE group was still less compared with that in the NE group (p

The effect of microstructures on strength, strain capacity and low temperature toughness of a micro-alloyed pipeline steel was elucidated. Five various dual-phase microstructures, namely, acicular ferrite and a small amount of (around 2 vol.%) polygonal ferrite (AF + PF), polygonal ferrite and bainite (PF + B), polygonal ferrite and martensite/austenite islands (PF + M/A), polygonal ferrite and martensite (PF + M) and elongated polygonal ferrite and martensite (ePF + M), have been studied. Experimental results show that AF + PF microstructure has high yield strength and excellent low temperature toughness, whereas its yield ratio is the highest. Polygonal ferrite-based dual-phase steels, PF + B, PF + M/A and PF + M microstructures show better strain capacity and low temperature toughness. The strain capacity and low temperature toughness of ePF + M microstructure are the worst due to its high strength. The relationship between microstructure, strength, strain capacity and toughness has been established. Based on the results, the optimum microstructure for a better combination of strength, strain capacity and toughness is suggested to be the one having appropriate polygonal ferrite as second phase in an acicular ferrite matrix.

By tactfully structuring a luminescent molecule as an accurate pH probe with aggregation-induced emission (AIE) feature, it is significant to overcome aggregation-caused quenching of emitted light in practice. Herein, we present a simple AIE-active fluorescence probe for pH detection on the basis of intramolecular charge transfer (ICT) with wide response range and high sensitivity reaction. The donor-acceptor-donor (D-A-D) style probe utilized a conjugated structural hybrid of the electron-withdrawing nitrile group and electron-donating hydroxyl as well as dimethylamino groups for fluorescent platform. The AIE-active probe possesses good fluorescence under water fraction up to 90% in mixed MeOH/water system. Furthermore, it can be used in profiling and visualization of pH detection in MeOH/water system at fw = 90% under UV 365 nm lamp. What’s more, the probe can be employed to be a broad range test paper of pH detection, paving the way for low-cost practical applications.

The development of small, energy-efficient artificial intelligence edge devices is limited in conventional computing architectures by the need to transfer data between the processor and memory. Non-volatile compute-in-memory (nvCIM) architectures have the potential to overcome such issues, but the development of high-bit-precision configurations required for dot-product operations remains challenging. In particular, input–output parallelism and cell-area limitations, as well as signal margin degradation, computing latency in multibit analogue readout operations and manufacturing challenges, still need to be addressed. Here we report a 2 Mb nvCIM macro (which combines memory cells and related peripheral circuitry) that is based on single-level cell resistive random-access memory devices and is fabricated in a 22 nm complementary metal–oxide–semiconductor foundry process. Compared with previous nvCIM schemes, our macro can perform multibit dot-product operations with increased input–output parallelism, reduced cell-array area, improved accuracy, and reduced computing latency and energy consumption. The macro can, in particular, achieve latencies between 9.2 and 18.3 ns, and energy efficiencies between 146.21 and 36.61 tera-operations per second per watt, for binary and multibit input–weight–output configurations, respectively. Commercial complementary metal–oxide–semiconductor and resistive random-access memory technologies can be used to create multibit compute-in-memory circuits capable of fast and energy-efficient inference for use in small artificial intelligence edge devices.

The current pandemic of COVID-19 is fueled by more infectious emergent Omicron variants. Ongoing concerns of emergent variants include possible recombinants, as genome recombination is an important evolutionary mechanism for the emergence and re-emergence of human viral pathogens. In this study, we identified diverse recombination events between two Omicron major subvariants (BA.1 and BA.2) and other variants of concern (VOCs) and variants of interest (VOIs), suggesting that co-infection and subsequent genome recombination play important roles in the ongoing evolution of SARS-CoV-2. Through scanning high-quality completed Omicron spike gene sequences, 18 core mutations of BA.1 (frequency >99%) and 27 core mutations of BA.2 (nine more than BA.1) were identified, of which 15 are specific to Omicron. BA.1 subvariants share nine common amino acid mutations (three more than BA.2) in the spike protein with most VOCs, suggesting a possible recombination origin of Omicron from these VOCs. There are three more Alpha-related mutations in BA.1 than BA.2, and BA.1 is phylogenetically closer to Alpha than other variants. Revertant mutations are found in some dominant mutations (frequency >95%) in the BA.1. Most notably, multiple characteristic amino acid mutations in the Delta spike protein have been also identified in the “Deltacron”-like Omicron Variants isolated since November 11, 2021 in South Africa, which implies the recombination events occurring between the Omicron and Delta variants. Monitoring the evolving SARS-CoV-2 genomes especially for recombination is critically important for recognition of abrupt changes to viral attributes including its epitopes which may call for vaccine modifications.

Background Identification of potential novel targets for reversing resistance to Epidermal Growth Factor Receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) holds great promise for the treatment of relapsed lung adenocarcinoma (LUAD). In the present study, we aim to investigate the role of methyltransferase-like 7B (METTL7B) in inducing EGFR-TKIs resistance in LUAD and whether it could be a therapeutic target for reversing the resistance. Methods METTL7B-overexpressed LUAD cell lines, gefitinib and osimertinib-resistant Cell-Derived tumor Xenograft (CDX) and Patient-Derived tumor Xenograft (PDX) mouse models were employed to evaluate the role of METTL7B in TKIs resistance. Ultraperformance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) was used to identify the metabolites regulated by METTL7B. Methylated RNA immunoprecipitation (MeRIP)-qPCR analysis was performed to measure the N6-methyladenosine (m6A) status of mRNA of METTL7B targeted genes. Gold nanocluster-assisted delivery of siRNA targeting METTL7B (GNC-siMETTL7B) was applied to evaluate the effect of METTL7B in TKIs resistance. Results Increased expression of METTL7B was found in TKIs-resistant LUAD cells and overexpression of METTL7B in LUAD cells induced TKIs resistance both in vitro and in vivo. Activated ROS-metabolism was identified in METTL7B-overexpressed LUAD cells, accompanied with upregulated protein level of GPX4, HMOX1 and SOD1 and their enzymatic activities. Globally elevated m6A levels were found in METTL7B-overexpressed LUAD cells, which was reduced by knock-down of METTL7B. METTL7B induced m6A modification of GPX4, HMOX1 and SOD1 mRNA. Knock-down of METTL7B by siRNA re-sensitized LUAD cells to gefitinib and osimertinib both in vitro and in vivo. Conclusions This study uncovered a new critical link in METTL7B, glutathione metabolism and drug resistance. Our findings demonstrated that METTL7B inhibitors could be used for reversing TKIs resistance in LUAD patients.

Liver resection for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) offers a chance of cure, although survival is often limited. The actual 3-year survival and its associated prognostic factors have not been reported. A nationwide database of HCC patients with PVTT who underwent liver resection with ‘curative’ intent was analyzed. The clinicopathologic characteristics, the perioperative, and survival outcomes for the actual long-term survivors were compared with the non-long-term survivors (patients who died within 3 years of surgery). Univariable and multivariable regression analyses were performed to identify predictive factors associated with long-term survival outcomes. The study included 1590 patients with an actuarial 3-year survival of 16.6%, while the actual 3-year survival rate was 11.7%. There were 171 patients who survived for at least 3 years after surgery and 1290 who died within 3 years of surgery. Multivariable regression analysis revealed that total bilirubin > 17.1 μmol/l, AFP > 400 ng/ml, types of hepatectomy, extent of PVTT, intraoperative blood loss > 400 ml, tumor diameter > 5 cm, tumor encapsulation, R0 resection, liver cirrhosis, adjuvant TACE, postoperative early recurrence (

The morphology and characteristics of granular bainite (GB) in pipeline steels at different continuous cooling rates were investigated by scanning electron microscopy, transmission electron microscopy and electron back-scattered diffraction (EBSD). The results show that the morphology of ferrite matrix in GB turned from the lath sheaf structure into the nearly equiaxed large grain with the cooling rate decreasing from high (60 °C/s) to low (5–10 °C/s). At the medium cooling rate (20–40 °C/s), GB consisted of the irregular ferrite matrix, the granular martensite/austenite (M/A) constituents and abundant substructures inside. The formation of the irregular ferrite and substructure was attributed to the high-temperature recovery which occurred at relatively high-temperature stage before phase transformation. The granular morphology of M/A constituents was formed from the carbon-rich triple junctions which were produced by the multidirectional substructure interfaces converged with each other. Particularly, some martensite in M/A constituents was misoriented from the adjacent ferrite by very small misorientation angle, which could be characterized by the mean band contrast function of EBSD qualitatively or semiquantitatively.

PURPOSE: Inflammatory breast cancer (IBC) is an aggressive variant for which axillary lymph node dissection following neoadjuvant chemotherapy (NACT) remains standard of care. But with increasingly effective systemic therapy, it is unclear whether more limited axillary surgery may be appropriate in some IBC patients. We sought to examine whether extent of axillary lymph node (LN) surgery was associated with overall survival (OS) for IBC. METHODS: Female breast cancer patients with non-metastatic IBC (cT4d) diagnosed 2010–2014 were identified in the National Cancer Data Base. Cox proportional hazards modeling was used to estimate the association between extent of axillary surgery (≤9 vs ≥10 LNs removed) and OS after adjusting for covariates, including post-NACT nodal status (ypN0 vs ypN1–3) and radiotherapy receipt (yes/no). RESULTS: 3,471 patients were included: 597 (17.2%) had cN0 disease, 1,833 (52.8%) had cN1 disease, and 1,041 (30%) had cN2–3 disease. 49.9% of cN0 patients were confirmed to be ypN0 on post-NACT surgical pathology. Being ypN0 (vs ypN1–3) was associated with improved adjusted OS for all patients. Radiotherapy was associated with improved adjusted OS for cN1 and cN2–3 patients but not for cN0 patients. Regardless of ypN status, there was a trend towards improved adjusted OS with having ≥10 (vs ≤9) LNs removed for cN2–3 patients (HR 0.78, 95% CI 0.60–1.01, p=0.06) but not for cN0 patients (p=0.83). CONCLUSIONS: A majority of IBC patients in our study presented with node-positive disease, and for those presenting with cN2–3 disease, more extensive axillary surgery is potentially associated with improved survival. For cN0 patients, however, more extensive axillary surgery was not associated with a survival benefit, suggesting an opportunity for more personalized care.