Gene association analysis to determine the causal relationship between immune-mediated inflammatory diseases and frozen shoulder.

Multiple studies have indicated a potential correlation between immune-mediated inflammatory diseases (IMIDs) and Frozen shoulder (FS). To explore the genetic causal relationship between IMIDs and FS using 2-sample Mendelian randomization (MR) analysis. Genome-wide association study (GWAS) summary data for FS were obtained from Green's study, while data for 10 IMIDs were sourced from the FinnGen Consortium. The MR analysis was performed using inverse variance weighting, MR Egger, and weighted median methods. IVW, as the primary MR analysis technique, was complemented with other sensitivity analyses to validate the robustness of the results. Additionally, reverse MR analysis was further conducted to investigate the presence of reverse causal relationships. In the forward MR analysis, genetically determined 4 IMIDs are causally associated with FS: rheumatoid arthritis (odds ratio [OR] (95% confidence interval [95% CI]) = 1.05 [1.02-1.09], P < .01); type 1 diabetes (OR [95% CI] = 1.06 [1.03-1.09], P < .01); hypothyroidism (OR [95% CI] = 1.07 [1.01-1.14], P = .02); and Celiac disease (OR [95% CI] = 1.02 [1.01-1.04], P = .01). However, no causal relationship was found between 6 IMIDs (autoimmune hyperthyroidism, Crohn disease, ulcerative colitis, psoriasis, sicca syndrome and systemic lupus erythematosus) and FS. Sensitivity analyses did not detect any heterogeneity or horizontal pleiotropy. In the reverse MR analysis, no causal relationship was observed between FS and IMIDs. In conclusion, this MR study suggests a potential causal relationship between rheumatoid arthritis, type 1 diabetes, hypothyroidism, and Celiac disease in the onset and development of FS. Nevertheless, more basic and clinical research will be needed in the future to support our findings.

Simulation and parameter determination of the net sorption of phenanthrene by sediment particles.

The distribution of polycyclic aromatic hydrocarbons (PAHs) in the ocean is affected by the sorption-desorption process of sediment particles. This process is determined by the concentration of PAHs in seawater, water temperature, and organic matter content of sediment particles. Quantitative relationships between the net sorption rates (=the difference of sorption and desorption rates) and these factors have not been established yet and used in PAH transport models. In this study, phenanthrene was chosen as the representative of PAHs. Three groups of experimental data were collected to address the dependence of the net sorption processes on the initial concentration, water temperature, and organic carbon content representing organic matter content. One-site and two-compartment mass-transfer models were tested to represent the experimental data using various parameters. The results showed that the two-compartment mass-transfer model performed better than the one-site mass-transfer model. The parameters of the two-compartment mass-transfer model include the sorption rate coefficients kafand kas (L g-1 min-1), and the desorption rate coefficients kdf and kds (min-1). The parameters at different temperatures and organic carbon contents were obtained by numerical simulations. Linear relationships were obtained between the parameters and water temperature, as well as organic carbon content. kaf, kas and kdf decreased linearly, while kds increased linearly with temperature. kaf, kas and kdf increased linearly, while kds decreased linearly with organic carbon content. The r2 values between the simulation results based on the relationships and the experimental results reached 0.96-0.99, which supports the application of the model to simulate sorption-desorption processes at different water temperatures and organic carbon contents in a realistic ocean.

Osr1-mediated mesothelial transition of liver mesenchymal cells exacerbates fibrotic liver damage.

In chronic liver diseases, hepatic stellate cells (HSCs) are induced to form the myofibroblasts responsible for scar formation, leading to liver fibrosis and cirrhosis. Here, single-cell RNA sequencing with in vivo lineage tracing in nonalcoholic steatohepatitis (NASH) model mice reveals a subpopulation of HSCs transitioning back to a state resembling their developmental precursors, mesothelial cells (MCs), after liver injury. These damage-associated intermediates between HSCs and MCs (DIHMs) can be traced with a dual recombinase system by labeling Krt19-expressing cells within prelabeled Pdgfrb+ HSCs, and DIHMs highly express inflammation- and fibrosis-associated genes. Cre and Dre-inducible depletion of DIHMs by administering diphtheria toxin reduces liver fibrosis and alleviates liver damage in NASH model mice. Importantly, knockdown of Osr1, a zinc finger transcription factor of the OSR gene family, can block DIHM induction in vitro. Conditional knockout Osr1 in Pdgfrb-expressing mesenchymal cells in NASH model mice can reduce liver fibrosis in vivo. Our study collectively uncovers an injury-induced developmental reversion process wherein HSCs undergo what we call a mesenchymal-to-mesothelial transition, which can be targeted to develop interventions to treat chronic liver diseases.

Influence of two kinds of clearance joints on the dynamics of planar mechanical system based on a modified contact force model.

This study takes the slider-crank mechanism with revolute joint and translational joint as the research object and studies the contact force model of the clearance joint and the influence of the hybrid clearance joints on the nonlinear dynamic behavior of the mechanism. A modified contact force model is established based on the simplified elastic oscillator model, which can be used as a normal force in clearance joint. In the new contact force model, the component n of the indentation depth can be arbitrarily selected and it can support the calculation of contact force for both fully elastic recovery, non-elastic recovery and fully inelastic recovery. Based on the LuGre friction model, the tangential friction model of the clearance joint is given. Thus, the normal force and tangential force during the dynamic contact of the clearance joint are formed. Combining Lagrange's equations of the first kind with the modified normal force and tangential friction force, the dynamic equations of the multi-body system with clearance joints are established. The Baumgarte stabilization method is used to improve the numerical stability. The correctness of the dynamic prediction model in the mechanism with clearance joint is verified by experiment. The dynamic analysis of the slider-crank mechanism with mixed clearance joints shows that the revolute clearance joint has a greater influence on the mechanism than the translational clearance, and the revolute clearance joint plays a leading role in the dynamic response.

High-throughput functional screen identifies YWHAZ as a key regulator of pancreatic cancer metastasis.

Pancreatic cancer is a leading cause of cancer death due to its early metastasis and limited response to the current therapies. Metastasis is a complicated multistep process, which is determined by complex genetic alterations. Despite the identification of many metastasis-related genes, distinguishing the drivers from numerous passengers and establishing the causality in cancer pathophysiology remains challenging. Here, we established a high-throughput and piggyBac transposon-based genetic screening platform, which enables either reduced or increased expression of chromosomal genes near the incorporation site of the gene search vector cassette that contains a doxycycline-regulated promoter. Using this strategy, we identified YWHAZ as a key regulator of pancreatic cancer metastasis. We demonstrated that functional activation of Ywhaz by the gene search vector led to enhanced metastatic capability in mouse pancreatic cancer cells. The metastasis-promoting role of YWHAZ was further validated in human pancreatic cancer cells. Overexpression of YWHAZ resulted in more aggressive metastatic phenotypes in vitro and a shorter survival rate in vivo by modulating epithelial-to-mesenchymal transition. Hence, our study established a high-throughput screening method to investigate the functional relevance of novel genes and validated YWHAZ as a key regulator of pancreatic cancer metastasis.

Water excitation with LIBRE pulses in three-dimensional variable flip angle fast spin echo for fat-free and large field of view imaging at 3 tesla.

PURPOSE: To develop and evaluate a sequence in which water excitation with lipid insensitive binomial off-resonant radio frequency excitation (LIBRE) pulses is incorporated into three-dimensional (3D) variable flip angle fast spin echo (LIBRE-vf-FSE) for fat-free and large field of view imaging at 3 Tesla (T). MATERIALS AND METHODS: Numerical simulation was conducted to optimize the parameters of LIBRE pulses, including the flip angle, pulse duration, and frequency offset, for maximizing the fat suppression effect of the proposed LIBRE-vf-FSE sequence. The sequence was then implemented at 3 T and assessed in phantoms, lower extremity imaging of 8 healthy volunteers, and head/neck imaging of 5 healthy volunteers. Conventional water excitation (WE) and fat saturation (FatSat) were also performed for comparison. Signal-to-noise ratio (SNR) of fat and contrast-to-noise ratio (CNR) between fat and water were used to evaluate the level of fat suppression. Standard deviation (SD) of SNR was used to evaluate the uniformity of fat suppression. RESULTS: The numerical simulation demonstrated that LIBRE-vf-FSE enables large volume imaging with uniform fat suppression, which was further confirmed by phantom and healthy volunteer experiments. LIBRE provided the lowest fat SNR and offered more uniform fat suppression compared with the WE and FatSat. Specifically, average oil SNRs obtained by LIBRE (1.10 ms, 360 Hz, and 60°), WE, and FatSat were (180.1 vs. 280.2 vs. 811.2) in phantom experiments, and average fat SNRs and SDs in legs obtained by LIBRE (1.10 ms, 360 Hz, and 60°), WE, and FatSat were (85.1 vs. 105.0 vs. 105.1) and (22.4 vs. 27.4 vs. 56.4) in vivo experiments, respectively. CONCLUSION: The proposed LIBRE-vf-FSE sequence allows for fat suppression and large field of view imaging at 3 T. It could be an alternative approach for fat-free vf-FSE scan.

HMMR promotes peritoneal implantation of gastric cancer by increasing cell-cell interactions.

BACKGROUND: Distant metastasis is the prominent factor for cancer-induced death of gastric cancer in which peritoneum is one of the dominating targets of gastric cancer metastasis. However, there is still a lack of effective predictive indicators and treatment methods for gastric cancer patients with peritoneal metastasis. METHODS: A clustering assay was used to investigate the cell aggregates formation ability. While the soft agar assay and anoikis assay were performed to detect the anchorage-independent growth and anoikis-resistant ability respectively. Luciferase activity assay, western blotting and immunofluorescence were used to explore the effect of HMMR on AKT signaling activity. The peritoneal implantation model was examined to explore the role of HMMR in vivo. RESULTS: Silencing of HMMR expression markedly reduced the peritoneal metastasis of gastric cancer cells through reducing cell-cell interactions. Mechanistically, HA-HMMR could activate Akt signaling, thus succeeding in distant colonization and metastatic outgrowth. Importantly, inducible depletion of HMMR significantly abrogates peritoneal implantation of gastric cancer in vitro and in vivo. CONCLUSION: Our study highlights that HMMR promotes peritoneal implantation of gastric cancer. A better understanding of HMMR's functions and mechanism might provide a novel therapeutic target and prognostic marker for metastatic gastric cancer.

Nrf2 expands the intracellular pool of the chaperone AHSP in a cellular model of ß-thalassemia.

In ß-thalassemia, free α-globin chains are unstable and tend to aggregate or degrade, releasing toxic heme, porphyrins and iron, which produce reactive oxygen species (ROS). α-Hemoglobin-stabilizing protein (AHSP) is a potential modifier of ß-thalassemia due to its ability to escort free α-globin and inhibit the cellular production of ROS. The influence of AHSP on the redox equilibrium raises the question of whether AHSP expression is regulated by components of ROS signaling pathways and/or canonical redox proteins. Here, we report that AHSP expression in K562 cells could be stimulated by NFE2-related factor 2 (Nrf2) and its agonist tert-butylhydroquinone (tBHQ). This tBHQ-induced increase in AHSP expression was also observed in Ter119+ mouse erythroblasts at each individual stage during terminal erythroid differentiation. We further report that the AHSP level was elevated in α-globin-overexpressing K562 cells and staged erythroblasts from ßIVS-2-654 thalassemic mice. tBHQ treatment partially alleviated, whereas Nrf2 or AHSP knockdown exacerbated, α-globin precipitation and ROS production in fetal liver-derived thalassemic erythroid cells. MafG and Nrf2 occupancy at the MARE-1 site downstream of the AHSP transcription start site was detected in K562 cells. Finally, we show that MafG facilitated the activation of the AHSP gene in K562 cells by Nrf2. Our results demonstrate Nrf2-mediated feedback regulation of AHSP in response to excess α-globin, as occurs in ß-thalassemia.

Atomic Pt Promoted N-Doped Carbon as Novel Negative Electrode for Li-Ion Batteries.

In this work, platinum single-atom enhanced mushroom-based carbon (Pt1/MC) materials have been facilely synthesized and served as novel electrode materials in lithium-ion batteries (LIBs). The as-synthesized Pt1/MC active material shows a uniform dispersion of isolated Pt atoms on an MC support with high specific surface area and large total pore volume. As a negative electrode material for LIBs, the Pt1/MC exhibits excellent electrochemical properties, which retains a capacity of 846 mA h g-1 after 800 cycles at 2 A g-1 and 349 mA h g-1 (near to the theoretical capacity of graphite) after 6000 cycles at a high current density of 5 A g-1. The remarkable high capacity and excellent cycling stability can be attributed to their porous nanostructures and atomic-Pt-enhanced lithium-ion storage. Atomic Pt can compound with Li+ ions to form a platinum-lithium alloy during the discharge and charge process. Density functional theory (DFT) calculations are performed to verify that the PtLi5 alloy is the most stable intermedium on the MC substrate, which further enhances the lithiation and delithiation kinetics. This novel perspective is helpful to explore next-generation negative electrode materials with high capacities and good stabilities for LIBs.

Acyl-CoA dehydrogenase long chain expression is associated with esophageal squamous cell carcinoma progression and poor prognosis.

BACKGROUND: Acyl-CoA dehydrogenase long chain (ACADL) was revealed to have a correlation with malignant progression of cancer. However, whether ACADL plays a role in clinical therapy remains unclear. The clinicopathological role of ACADL in esophageal squamous cell carcinoma (ESCC) will be discussed in this study. MATERIALS AND METHODS: The expression of ACADL was analyzed via real-time PCR and Western blotting to assess mRNA and protein levels in ESCC cell lines and normal esophageal epithelial cells (NEECs), in six paired ESCC tumors and relative normal tissues. Furthermore, immunohistochemical staining was performed on 135 paraffin-embedded ESCC specimens to assess ACADL expression. The clinicopathological significance of ACADL expression was further investigated via survival analysis and Cox regression analysis. RESULTS: ACADL was found to be markedly upregulated in ESCC cell lines when compared with NEECs. Moreover, various experiments such as quantitative real-time PCR, Western blot, and immunohistochemical analyses all revealed that ACADL expression was increased in all six paired ESCC tumors and matched normal tissues. Furthermore, immunohistochemical analysis revealed an increased level of ACADL protein expression in all 135 paraffin-embedded samples from ESCC patients, which increased with disease progression. CONCLUSION: We demonstrated that ACADL is overexpressed in ESCC, both in cell lines and clinical specimens. ACADL is found to be a vital regulator in ESCC progression and can predict a worse outcome for ESCC patients, suggesting that ACADL might be a valuable molecule to be targeted for clinical therapy of ESCC treatment.

Overexpression of CDCA7 predicts poor prognosis and induces EZH2-mediated progression of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with high proliferative and metastatic phenotypes. CDCA7, a new member of the cell division cycle associated family of genes, is involved in embryonic development and dysregulated in various types of human cancer. However, the biological role and molecular mechanism of CDCA7 in TNBC have not been defined. Herein, we found that CDCA7 was preferentially and markedly expressed in TNBC cell lines and tissues. High expression of CDCA7 was associated with metastatic relapse status and predicted poorer disease-free survival in patients with TNBC. We observed that CDCA7 silencing in TNBC cell lines effectively impaired cell proliferation, invasion and migration in vitro. Importantly, depletion of CDCA7 strongly reduced the tumorigenicity and distant colonization capacities of TNBC cells in vivo. Furthermore, CDCA7 increased the expression of EZH2, a marker of aggressive breast cancer that is involved in tumor progression, by enhancing the transcriptional activity of its promoter. This increase in EZH2 expression was essential for the CDCA7-mediated effects on TNBC progression. Finally, our immunohistochemical analysis revealed that the CDCA7/EZH2 axis was clinical relevant. These findings suggest CDCA7 plays a crucial role in TNBC progression by transcriptionally upregulating EZH2 and might be a potential prognostic factor and therapeutic target in TNBC.

Selecting an appropriate interestingness measure to evaluate the correlation between Chinese medicine syndrome elements and symptoms.

To select the best interestingness measure appropriate for evaluating the correlation between Chinese medicine (CM) syndrome elements and symptoms, 60 objective interestingness measures were selected from different subjects. Firstly, a hypothesis for a good measure was proposed. Based on the hypothesis, an experiment was designed to evaluate the measures. The experiment was based on the clinical record database of past dynasties including 51 186 clinical cases. The selected data set in this study had 44 600 records. Cold and heat were selected as the experimental CM syndrome elements. Three indicators calculated according to the distances between two CM syndrome elements were obtained in the experiment and combined into one indicator. The Z score, ϕ-coefficient, and Kappa were selected from 60 measures after the experiment. The Z score and ϕ-coefficient were selected according to subjective interestingness. Finally, the ϕ-coefficient was selected as the best measure for its low computational complexity. The method introduced in this paper may be used in other similar territories.

The TCM pattern of the six-zang and six-fu organs can be simplified into the pattern of five-zang and one-fu organs.

OBJECTIVE: To simplify the TCM pattern of the zang-fu organs. METHODS: A database of zang-fu syndromes was established. The relationship between the zang-fu syndromes was analyzed by means of frequency analysis, association rule, and phi-coefficient correlation. RESULTS: The six zang-fu organs of the heart, liver, spleen, lung, kidney, and stomach prove to be the main components of the zang-fu pattern. The large intestine, small intestine, gallbladder, bladder, triple energizer, and pericardium have strong association and positive correlation with the above-mentioned six zang-fu organs, and their clinical symptoms can all be included into the symptoms of these six zang-fu organs. CONCLUSION: The traditional TCM pattern of six-zang and six-fu can be simplified into five-zang and one-fu.