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Cancer metastasis is an extremely complex process affected by many factors. An acidic microenvironment can drive cancer cell migration towards blood vessels while also hampering immune cell activity. Here, we identified a mechanism mediated by sialyltransferases that induces an acidic tumor permissive microenvironment (ATPME) in BRCA1-mutant and most BRCA1-low breast cancers. Hypersialylation mediated by ST8SIA4 perturbed the mammary epithelial bilayer structure and generated an ATPME and immunosuppressive microenvironment with increased PD-L1 and PD1 expression. Mechanistically, BRCA1 deficiency increased expression of VEGF-A and IL6 to activate TGFβ-ST8SIA4 signaling. High levels of ST8SIA4 led to accumulation of polysialic acid (PSA) on mammary epithelial membranes that facilitated escape of cancer cells from immunosurveillance, promoting metastasis and resistance to αPD1 treatment. The sialyltransferase inhibitor 3Fax-Peracetyl Neu5Ac neutralized the ATPME, sensitized cancers to immune checkpoint blockade by activating CD8 T cells, and inhibited tumor growth and metastasis. Together, these findings identify a potential therapeutic option for cancers with a high level of PSA.

End-stage kidney disease and mild cognitive impairment (ESKD-MCI) affect the quality of life and long-term treatment outcomes of patients affected by these diseases. Clarifying the morphological changes from brain injuries in ESKD-MCI and their relationship with clinical features is helpful for the early identification and intervention of MCI, before it progresses irreversible dementia. This study gathered data from 23 patients with ESKD-MCI, 24 patients with ESKD and non-cognitive impairment (NCI), and 27 health controls (HCs). Structural magnetic resonance studies, cognitive assessments, and general clinical data were collected from all of the participants. Voxel-based morphometry analysis was performed to compare grey matter (GM) volume differences between the groups. The patients’ GM maps and clinical features were subjected to univariate regression, to check for possible correlations. Patients with ESKD-MCI displayed significantly more impairments in multiple cognitive domains including global cognition, visuospatial and executive function, and memory, as compared with patients with ESKD-NCI. Using a more liberal threshold (P

Carotenoid (Car) pigments perform central roles in photosynthesis-related light harvesting (LH), photoprotection, and assembly of functional pigment-protein complexes. However, the relationships between Car depletion in the LH, assembly of the prokaryotic reaction center (RC)-LH complex, and quinone exchange are not fully understood. Here, we analyzed native RC-LH (nRC-LH) and Car-depleted RC-LH (dRC-LH) complexes in Roseiflexus castenholzii, a chlorosome-less filamentous anoxygenic phototroph that forms the deepest branch of photosynthetic bacteria. Newly identified exterior Cars functioned with the bacteriochlorophyll B800 to block the proposed quinone channel between LHαβ subunits in the nRC-LH, forming a sealed LH ring that was disrupted by transmembrane helices from cytochrome c and subunit X to allow quinone shuttling. dRC-LH lacked subunit X, leading to an exposed LH ring with a larger opening, which together accelerated the quinone exchange rate. We also assigned amino acid sequences of subunit X and two hypothetical proteins Y and Z that functioned in forming the quinone channel and stabilizing the RC-LH interactions. This study reveals the structural basis by which Cars assembly regulates the architecture and quinone exchange of bacterial RC-LH complexes. These findings mark an important step forward in understanding the evolution and diversity of prokaryotic photosynthetic apparatus.

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The α-subunit of eukaryotic initiation factor 2 (eIF2α) is a key translation regulator that plays an important role in cellular stress responses. In the present study, we investigated how eIF2α phosphorylation can be regulated by a tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) and how such regulation is used by PTEN-deficient hepatocytes to adapt and cope with oxidative stress. We found that eIF2α was hyperphosphorylated when Pten was deleted, and this process was AKT dependent. Consistent with this finding, we found that the Pten-null cells developed resistance to oxidative glutamate and H2O2-induced cellular toxicity. We showed that the messenger level of CReP (constitutive repressor of eIF2α phosphorylation), a constitutive phosphatase of eIF2α, was downregulated in Pten-null hepatocytes, providing a possible mechanism through which PTEN/AKT pathway regulates eIF2α phosphorylation. Ectopic expression of CReP restored the sensitivity of the Pten mutant hepatocytes to oxidative stress, confirming the functional significance of the downregulated CReP and upregulated phospho-eIF2α in the resistance of Pten mutant hepatocytes to cellular stress. In summary, our study suggested a novel role of PTEN in regulating stress response through modulating the CReP/eIF2α pathway. Mol Cancer Res; 9(12); 1708–17. ©2011 AACR.

SMAD4 loss-of-function mutations have been frequently observed in colorectal cancer (CRC) and are recognized as a drug target for therapeutic exploitation. In this study, we performed a synthetic lethal drug screening with SMAD4-isogenic CRC cells and found that aurora kinase A (AURKA) inhibition is synthetic lethal with SMAD4 loss. Inhibition of AURKA selectively inhibited the growth of SMAD4

Supplementary Figure 1 from Absence of the Full-Length Breast Cancer–Associated Gene-1 Leads to Increased Expression of Insulin-Like Growth Factor Signaling Axis Members

The tumor suppressor BRCA1 interacts with many proteins and undergoes multiple modifications on DNA damage. ATM, a key molecule of the DNA damage response, phosphorylates S1189 of BRCA1 after γ-irradiation. S1189 of BRCA1 is known as a unique ATM phosphorylation site in BRCA1 exon 11. To study the functions of ATM-dependent phosphorylation of BRCA1-S1189, we generated a mouse model carrying a mutation of S1152A (S1152 in mouse Brca1 corresponds to S1189 in human BRCA1) by gene targeting. Brca1S1152A/S1152A mice were born at the expected ratio, unlike that seen in previous studies of Brca1-null mice. However, 36% of Brca1S1152A/S1152A mice exhibited aging-like phenotypes including growth retardation, skin abnormalities, and delay of the mammary gland morphogenesis, with an increase in apoptosis. Mutant mice were hypersensitive to high doses of γ-irradiation, displaying shortened life span and reduction in intestinal villus size, associated with increased apoptosis. Aging-unaffected 18-month-old Brca1S1152A/S1152A female mice also showed mammary gland abnormalities with increased levels of cyclin D1 and phospho-ER-α, such as Brca1-Δ11 mutation. On low-dose γ-irradiation, they suffered a marked increase in tumor formation with an abnormal coat pattern. Furthermore, Brca1S1152A/S1152A embryonic fibroblasts failed to accumulate p53 on γ-irradiation with delayed phosphorylation of p53-S23. These observations indicate that ATM-mediated phosphorylation of S1189 is required for BRCA1 functions in the modulation of DNA damage response and in the suppression of tumor formation by regulating p53 and apoptosis. [Cancer Res 2009;69(24):9291–300]

The breast cancer–associated gene-1 (BRCA1) plays many important functions in multiple biological processes/pathways. Mice homozygous for a targeted deletion of full-length BRCA1 (Brca1Δ11/Δ11) display both increased tumorigenesis and premature aging, yet molecular mechanisms underlying these defects remain elusive. Here, we show that Brca1 deficiency leads to increased expression of several insulin-like growth factor (IGF) signaling axis members in multiple experimental systems, including BRCA1-deficient mice, primary mammary tumors, and cultured human cells. Furthermore, we provide evidence that activation of IGF signaling by BRCA1 deficiency can also occur in a p53-independent fashion. Our data indicate that BRCA1 interacts with the IRS-1 promoter and inhibits its activity that is associated with epigenetic modification of histone H3 and histone H4 to a transcriptional repression chromatin configuration. We further show that BRCA1-deficient mammary tumor cells exhibit high levels of IRS-1, and acute suppression of Irs-1 using RNA interference significantly inhibits growth of these cells. Those observations provide a molecular insight in understanding both fundamental and therapeutic BRCA1-associated tumorigenesis and aging. (Cancer Res 2006; 66(14): 7151-7)

Supplementary Methods and Figure 1 from Impaired Skin and Mammary Gland Development and Increased γ-Irradiation–Induced Tumorigenesis in Mice Carrying a Mutation of S1152-ATM Phosphorylation Site in Brca1

Breast cancer–associated gene 1 ( Brca1 ) deficiency induces the onset of breast cancer formation, accompanied with extensive genetic alterations. Here, we used both the sleeping beauty transposon mutagenesis system and CRISPR-Cas9–mediated genome-wide screening in mice to identify potential genetic alterations that act synergistically with Brca1 deficiency to promote tumorignesis. Both approaches identified Cullin-5 as a tumor suppressor, whose mutation enabled Brca1 -deficient cell survival and accelerated tumorigenesis by orchestrating tumor microenvironment. Cullin-5 suppresses cell growth through ubiquitylating and degrading adenosine 3′,5′-monophosphate–responsive element binding protein 1 (CREB1), especially under protein damage condition. Meanwhile, Cullin-5 deficiency activated CREB1-CCL2 signaling and resulted in the accumulation of monocytes and polymorphonuclear myeloid–derived suppressor cells, reduction of T cells that benefit tumor progression in both Brca1 -deficient cells and wild-type cells. Blocking CREB1 activity either through gene knockout or specific inhibitor treatment suppressed changes in the tumor microenvironment caused by Cullin-5 deficiency and blocked tumor progression.

The interplay among mitogenic signaling pathways is crucial for proper embryogenesis. These pathways collaboratively act through intracellular master regulators to determine specific cell fates. Identifying the master regulators is critical to understanding embryogenesis and to developing new applications of pluripotent stem cells. In this report, we demonstrate protein kinase C (PKC) as an intrinsic master switch between embryonic and extraembryonic cell fates in the differentiation of human pluripotent stem cells (hPSCs). PKCs are essential to induce the extraembryonic lineage downstream of BMP4 and other mitogenic modulators. PKC-alpha (PKCα) suppresses BMP4-induced mesoderm differentiation, and PKC-delta (PKCδ) is required for trophoblast cell fate. PKC activation overrides mesoderm induction conditions and leads to extraembryonic fate. In contrast, PKC inhibition leads to β-catenin (CTNNB1) activation, switching cell fate from trophoblast to mesoderm lineages. This study establishes PKC as a signaling boundary directing the segregation of extraembryonic and embryonic lineages. The manipulation of intrinsic PKC activity could greatly enhance cell differentiation under mitogenic regulation in stem cell applications.

Methods: Our study mainly used The Cancer Genome Atlas (TCGA) LIHC database and the gene expression profiles of GSE54236 from the Gene Expression Omnibus (GEO) to explore the differential co-expression genes between LIHC and normal tissues. The differential co-expression genes were extracted by Weighted Gene Co-expression Network Analysis (WGCNA) and differential gene expression analysis methods. The Genetic Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were carried out to annotate the function of differential genes. Then the hub genes were validated using protein-protein interaction (PPI) network. And the expression level and prognostic analysis were performed. The probable associations between the expression of hub genes and both tumor purity and infiltration of immune cells was explored by TIMER. Results: A total of 68 differential co-expression genes were extracted. These genes were mainly enriched in complement activation (biological process), collagen trimer (cellular component), carbohydrate binding and receptor ligand activity (molecular function) and cytokine−cytokine receptor interaction. Then we demonstrated that the 10 hub genes (CFP, CLEC1B, CLEC4G, CLEC4M, FCN2, FCN3, PAMR1 and TIMD4) were weakly expressed in LIHC tissues, and worse overall survival (OS) and disease-free survival (DFS) in LIHC patients were associated with the lower expression of CFP, CLEC1B, FCN3 and TIMD4. Ten hub genes had positive association with tumor purity. Conclusion: CFP, CLEC1B, FCN3 and TIMD4 could serve as novel potential molecular targets for prognosis prediction in LIHC.

Acute myeloid leukaemia (AML) is a biologically heterogeneous disease with an overall poor prognosis; thus, novel therapeutic approaches are needed. Our previous studies showed that 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), a new derivative of all-trans retinoic acid (ATRA), could induce AML cell differentiation and cycle arrest. The current study aimed to determine the potential pharmacological mechanisms of ATPR therapies against AML. Our findings showed that E2A was overexpressed in AML specimens and cell lines, and mediate AML development by inactivating the P53 pathway. The findings indicated that E2A expression and activity decreased with ATPR treatment. Furthermore, we determined that E2A inhibition could enhance the effect of ATPR-induced AML cell differentiation and cycle arrest, whereas E2A overexpression could reverse this effect, suggesting that the E2A gene plays a crucial role in AML. We identified P53 and c-Myc were downstream pathways and targets for silencing E2A cells using RNA sequencing, which are involved in the progression of AML. Taken together, these results confirmed that ATPR inhibited the expression of E2A/c-Myc, which led to the activation of the P53 pathway, and induced cell differentiation and cycle arrest in AML.

The charged CD-based membrane can precisely discriminate molecules with different charges, molecular weights, or shapes, which was determined by the inner cavities of CDs, outer spaces between CDs, and quaternary ammonium groups of the CD network.

Capturing and detecting Fe3+ ions in aqueous solution is of great significance in biological systems as well as the water treatment industry. Herein, pyrene-modified cellulose nanocrystal (CNC-1-Pyr) acting as a fluorescent probe was prepared by a one-step esterification reaction, which shows geometry relaxation under UV-light excitation. Experiments and density functional theory-based simulations revealed that the structural geometry relaxation is controlled by the electron excitation and fluorescence emission. The S1 state of CNC-1-Pyr provides a conformation match for coordination with Fe3+ under the excitation of UV light, facilitating the detecting and capturing of Fe3+ efficiently.

Background: The primary aim of this study was to investigate the prognostic value of peripheral blood lymphocyte subsets in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). Methods: From 2018 to 2019, 82 patients diagnosed with stage IIIB-IV NSCLC at Zhejiang Cancer Hospital were recruited for this study. Peripheral blood lymphocyte subsets of NSCLC patients were analyzed using flow cytometry before and after ICI treatment. The relationship between the percentage of peripheral blood lymphocyte subsets, clinicopathological features, progression-free survival (PFS), and overall survival (OS) was identified by correlation heat map, Kaplan-Meier curve, log-rank test, and Cox regression analysis. Results: The CD4/CD8 ratio and the percentage of B cells was decreased after ICI treatment. Furthermore, the percentage of CD3(+) T cells, natural killer (NK) cells, and natural killer T (NKT) cells before ICI treatment was associated with brain metastases, the proportion of CD3(+)CD4(+) T cells before ICI treatment was related to epidermal growth factor receptor (EGFR) status, the CD4/CD8 ratio before ICI treatment was correlated to pathology, the ratio of B cells before ICI treatment was related to therapeutic regimen, and the percentage of NKT cells before ICI treatment was associated with use of radiotherapy. Furthermore, univariate survival analysis revealed that low percentage of B cells forecasted a poor OS for NSCLC patients with ICI treatment. In addition, the nomogram developed by percentages of peripheral blood lymphocyte subsets could determine survival probability and survival time of NSCLC patients with immunotherapy. Conclusions: ICI treatment induced changes in the percentage of peripheral blood lymphocyte subsets, which had prognostic value for brain metastases, radiotherapy, EGFR status, pathology, and therapeutic regimen, along with prognostic value, for NSCLC patients treated with ICIs.

Forest Park plays a decisive role in ecotourism, because of its ability to provide visitors with a close natural experience. In the construction of urban ecological civilization,Forest Park also plays an indispensable part.In order to make the Forest Park healthy and orderly development, this articlechooses Fuzhou National Forest Park as an example, based on the AVC theory, combined with the questionnaire survey, and then draw out the factors that significantly affected the comprehensive evaluation of tourists,Finally, the results are summarized and discussed in order to guide the development and construction of Forest Park.The results showed that: (1) The overall evaluation of Fuzhou National Forest Park by tourists reached "excellent" class; (2) Attraction> vitality> capacity of tourists in the three comprehensive evaluation points. Among them, the overall rating of attraction and vitality is "excellent" and the capacity is only "good"; (3) In the indicator level, the comprehensive evaluation level of tourists with 9 indicators reached "excellent", 11 indicators comprehensive evaluation rating of "good"; (4) Pearson correlation coefficient analysis found: The architectural style, soundscape, customs, comfort, signage, external traffic facilities and fitness facilities are the significant factors that affect the comprehensive evaluation of tourists at Fuzhou National Forest Park. Analyzing the 20 indicators’ Importance - Comprehensive evaluation, we draw out the development of the advantages and disadvantages in Fuzhou National Forest Park, for each quadrant put forward the corresponding development strategy. Fuzhou National Forest Park comprehensive evaluation of excellent level. However, there is a certain lack of infrastructure construction. In the future development should pay attention to the harmonious development of the three forces, Maintain its unique attraction, Strong its vitality, focus on the development of its capacity, that Fuzhou National Forest Park can develop more and more healthy and orderly.

Androgen receptor (AR) plays a central role in driving prostate cancer (PCa) progression. How AR promotes this process is still not completely clear. Herein, we used single-cell transcriptome analysis to reconstruct the transcriptional network of AR in PCa. Our work shows AR directly regulates a set of signature genes in the ER-to-Golgi protein vesicle-mediated transport pathway. The expression of these genes is required for maximum androgen-dependent ER-to-Golgi trafficking, cell growth, and survival. Our analyses also reveal the signature genes are associated with PCa progression and prognosis. Moreover, we find inhibition of the ER-to-Golgi transport process with a small molecule enhanced antiandrogen-mediated tumor suppression of hormone-sensitive and insensitive PCa. Finally, we demonstrate AR collaborates with CREB3L2 in mediating ER-to-Golgi trafficking in PCa. In summary, our findings uncover a critical role for dysregulation of ER-to-Golgi trafficking expression and function in PCa progression, provide detailed mechanistic insights for how AR tightly controls this process, and highlight the prospect of targeting the ER-to-Golgi pathway as a therapeutic strategy for advanced PCa.

The “white hole effect” alters the driving environment during a tunnel’s exit phase, making it more difficult and uncertain for drivers to access information and control their behavior, thereby endangering traffic safety. Consequently, the driving risk at the exit of a long spiral tunnel served as the subject of this study, and the Jinjiazhuang spiral tunnel served as the object of the natural vehicle driving experiment. Following the theory of a non-linear autoregressive dynamic neural network, a vehicle speed prediction model based on driver characteristics was developed for the exit phase of the tunnel, taking driver expectations and behavioral changes into account. It also classifies the driver’s behavior during the tunnel’s exit phase to assess the risk posed by the driver’s behavior during the tunnel’s exit phase and determine a dynamic and safe comfort speed. The study’s results indicate that the driver’s behavioral load changed significantly as the vehicle approached the tunnel exit. At the exit of the spiral tunnel, the vehicle’s actual speed was 71 km/h, which is below the speed limit of 80 km/h. This demonstrates that the expected change in the driver’s behavior in the tunnel exit phase was substantial. Therefore, setting the emotional safety and comfort speed so that the driver maintains a smooth comfort level in the tunnel exit phase can reduce the tunnel exit driving risk. The results of this study provide a benchmark for tunnel traffic safety and lay the groundwork for further development of vehicle risk warning settings for the tunnel’s exit phase.

In this article, the flower-like, urchin-like, and rod-like ZnOs were synthesized by a convenient atmospheric hydrothermal method. The crystalline structures, morphologies, exposed crystal faces, and specific surface areas of the as-prepared ZnO samples were analyzed. Rhodamine B (RhB) was used as the simulated pollutant to evaluate the photocatalytic performance of the ZnO nanostructures. The flower-like ZnO prepared by controlled hydrothermal method at room temperature for 2 h displayed highest specific surface area and exposed more high active { 2 1 ¯ 1 ¯ 0 } \{2\bar{1}\bar{1}0\} facets compared to the other two morphologies of ZnO. In addition, within 2 h of the photocatalytic reaction, the flower-like ZnO results in 99.3% degradation of RhB and produces the most hydroxyl radicals (˙OH) 47.83 μmol/g and superoxide anions (˙ O 2 − {\text{O}}_{2}^{-} ) 102.78 μmol/g. Due to the existence of oxygen vacancies on the surface of { 2 1 ¯ 1 ¯ 0 } \{2\bar{1}\bar{1}0\} facets, the flower-like ZnO can efficiently catalyze the production of active oxygen, leading to the improvement in the photocatalytic efficiency.

Photocatalytic water splitting for hydrogen production was recognized as an effective strategy to obtain renewable energy for solving the environmental pollution and resource shortage crisis. Herein, we explored the solvothermal deposition method to successfully prepare blanket-like Bi2MoO6 coated on TiO2 nanotube arrays (TiO2 NTA/Bi2MoO6), and the TiO2 NTA/Bi2MoO6 photocatalyst showed outstanding visible light-driven photocatalytic water splitting capacity, and the hydrogen evolution rate achieved 129.26 μmol h-1 cm-2. Moreover, the sample also exhibited high photocatalytic pollutant decomposition performance. The remarkable photocatalytic performance was attributed to the synergistic effect of Bi2MoO6 and TiO2 NTA in the matched energy band location for solar absorption and carrier transportation. The synthesis and photocatalytic water splitting of Bi2MoO6/TiO2 NTA could afford the reproducible lesson for novel resource utilization of semiconductor photocatalysts.

In this work, a green Fe-doped TiO2 photocatalyst was successfully synthesized on Ti mesh through the chemical impregnation and anodization method. The influence of sample Fe-content on the photocatalytic performance was investigated in detail. Ordered TiO2 nanomesh was compactly decorated with nanospheres to form a novel photocatalyst Fe-doped TiO2 with anatase phase. Simultaneously, it exhibits higher light absorption intensity compared to the pristine TiO2 within the visible light range, and its absorption peak has a redshift. The VSM results showed that the sample has excellent magnetic properties. It is hard to achieve magnetic agglomeration after magnetic field removal, which benefits the strong recyclability and reusability of Fe-doped TiO2 photocatalyst. Importantly, this higher visible-light photoresponse of TiO2 was clearly obtained after Fe doping. When the Fe-content was 0.6 wt%, the degradation rate of methylene blue reached 87.9% under simulated sunlight irradiation for 2.5 h. The prepared nanocrystalline photocatalyst demonstrated excellent photocatalysis because of its prominent crystal morphology, strengthen light-absorption capacity, and commendable inhibition recombination of photo-induced electron-hole.

In order to clarify the characteristics of non-uniform water invasion in water-bearing gas reservoirs, it is necessary to introduce the non-uniformity coefficient (A) and water invasion constant (B) to characterize the non-uniformity degree of reservoir physical properties and the activity degree of peripheral water, respectively, based on the dual mechanism of water invasion to recharge the formation energy and seal off the gas in the reservoir. Then, the material balance method considering the phenomenon of water sealed gas was established. On this basis, the water invasion characteristic curve chart of water-bearing gas reservoirs was plotted, and the non-uniform water invasion mode was classified based on the example gas reservoir. And the following research results were obtained. First, in the water invasion characteristic curve chart of water-bearing gas reservoirs which is plotted based on the material balance method considering the influence of water sealed gas, the upper right area and the lower left area are defined as recharge area and seal area, respectively. By taking A = 0 and B = 2 as the boundary, the recharge area is divided into strong recharge area and weak recharge area. By taking A = 2 and B = 2 as the boundary, the seal area is divided into strong seal area and weak seal area. And correspondingly there are four water invasion modes, i.e., strong recharge, weak recharge, weak seal and strong seal. Second, for fractured gas reservoirs, the non-uniformity degree of reservoir physical properties is high, and water sealed gas can be formed easily after water invasion. The dimensionless relative pseudo-pressure data of this type of gas reservoir is located in the seal area of the water invasion characteristic curve chart. Third, for the gas reservoirs whose reservoir physical properties are relatively uniform, the dimensionless relative pseudo-pressure data is located in the recharge area of the water invasion characteristic curve chart, and the recharge effect of water invasion on formation energy is greater than the weakening effect of water sealed gas on formation energy. Fourth, with the increase of A, the non-uniformity degree of reservoir physical properties increases, the water invasion characteristic curve shifts from the upper right to the lower left, and the recovery factor of gas reservoir decreases continuously. With the increase of B, the recharge effect of water invasion on formation energy and the weakening effect of water sealed gas on formation energy are both weakened, the distribution range of water invasion characteristic curve narrows to the recharge/seal boundary, and the corresponding range of gas reservoir recovery factor also narrows.

Image restoration (IR) has been extensively studied with lots of excellent strategies accumulated over the years. However, most existing methods still have large room for improvement. In this paper, we boost an unsupervised iterative feature refinement model (IFR) with the enhanced high-dimensional deep mean-shift prior (EDMSP), termed IFR-EDMSP. The proposed model inherits the fantastic noise suppression characteristic of embedded network and the fine detail preservation ability of IFR model. Moreover, based on the fact that multiple implementations of artificial noise in prior learning improve underlying representation capability, three-sigma rule is adopted in IFR-EDMSP for accurate and robust results. Extensive experiments demonstrated that IFR-EDMSP outperforms the typical methods in compressed sensing, image deblurring and super-resolution.

Clinical research coordinators (CRCs) play an important role in the protection of clinical trial participants and maintenance of ethical standards. However, limited data are available on the ethical cognition of CRCs. Understanding the knowledge, attitude, and practices (KAP) of CRCs toward ethics is essential to protect study participants and improve their compliance.We conducted a descriptive, cross-sectional, quantitative study at 20 hospitals in Anhui province of China. A self-administered questionnaire was completed by 435 CRCs conducting clinical trials.The good knowledge, positive attitude, and good practice rates were 55.2%, 59.3%, and 79.5% respectively. Most CRCs (99.1%) were aware of the participants' rights. Only 127 (29.2%) and 140 (32.2%) CRCs were aware of measures to protect participants' rights and ethical guidelines regarding trials, respectively. In total, 59.6% of CRCs stated that ethical review might delay the start of a clinical trial. Marital status (odds ratio [OR] 0.47, 95% confidence interval [CI] 0.27-0.83), CRC work experience (OR 0.11, 95% CI 0.02-0.75), and educational background (OR 0.31, 95% CI 0.13-0.76) affected the knowledge of CRCs regarding ethics.Some deficiencies were observed in the ethical knowledge and behavior of CRCs. Interventions to improve the ethical training of CRCs regarding study participant protection, international guidelines, and the role of ethical committees are essential when conducting clinical trials. Validated instruments should be constructed to assess the effectiveness of ethical training and measure the KAP of CRCs toward ethics.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia and progressive joint destruction in the middle and late stages. Notably, activated rheumatoid arthritis synovial fibroblasts (RASFs) exhibit tumor-like features, including an increased proliferation rate that largely contributes to pannus formation and joint destruction. Our previous studies have demonstrated that acid-sensing ion channel 1a (ASIC1a) was highly expressed in RASFs, and acidic microenvironment of synovial fluid in patients with RA can activate ASIC1a to promote synovial inflammation, leading to the progression of RA. However, the role and possible mechanism of ASIC1a in RASF proliferation remains unclear. The present study aimed to investigate the effect of ASIC1a activation upon acidosis on RASF proliferation and its molecular mechanism in vivo and in vitro. The results of in vitro experiments showed that activation of ASIC1a upon acidosis promoted the proliferation of RASFs, which could be attenuated by the specific ASIC1a inhibitor Psalmotoxin-1 (PcTx-1) or specific siRNA for ASIC1a. Mechanistically, Wnt/β-catenin/c-Myc signaling pathway was involved in ASIC1a-induced RASF proliferation. The results of in vivo experiments indicated that intra-articular injection of PcTx-1 reduced synovial hyperplasia and ameliorated cartilage degradation in rats with adjuvant arthritis (AA). Collectively, these results suggest that activation of ASIC1a upon acidosis promotes RASF proliferation, and the mechanism may be related to Wnt/β-catenin/c-Myc pathway.

PTTM is a rare but fatal disease, characterized by endothelial intimal proliferation and pulmonary hypertension due to micro-vascular remodeling. In view of the poor prognosis, new effective strategies are urgently required.A 51-year-old woman was admitted to hospital for acute progressive dyspnea and dry cough. Clinical tests revealed hypercoagulable state and signs of severe pulmonary hypertension, without evidence of pulmonary embolism on contrast-enhanced CT. CT showed interlobular septal thickening and diffuse ground-glass opacity. Lung perfusion scan indicated multiple segment defect. Further right heart catherization proved a significant increase in pulmonary vascular resistance.A combination therapy of apatinib and selexipag was administered for treatment of PTTM. The conventional therapies of ventilation, anticoagulation and diuretic medicines were initiated after admission.Symptoms of PTTM were ameliorated with a reduction in pulmonary artery pressure. The resolution of interlobular septal thickening and ground-glass opacity on CT constituted the clinical benefits from treatment.Patient with PTTM will benefit from the combination strategy of apatinib, a VEGF-receptor antagonist, and selexipag, an oral prostacyclin receptor agonist.