Stanniocalcin-1 secreted by human umbilical mesenchymal stem cells regulates interleukin-10 expression via the PI3K/AKT/mTOR pathway in alveolar macrophages.

Acute respiratory distress syndrome (ARDS) is a syndrome of acute respiratory failure caused by infection, trauma, shock, aspiration or drug reaction. The pathogenesis of ARDS is characterized as an unregulated inflammatory storm, which causes endothelial and epithelial layer damage, leading to alveolar fluid accumulation and pulmonary edema. Previous studies have shown the potential role of mesenchymal stem cells (MSC) in combating the inflammatory cascade by increasing the anti-inflammatory mediator interleukin-10 (IL-10). However, the involved mechanisms are unclear. Here we investigated whether a key immunomodulatory regulator, stanniocalcin-1 (STC-1), was secreted by MSC to activate phosphoinositide 3-kinase/protein kinase B (PI3K/AKT)/ mammalian target of rapamycin (mTOR) signaling pathway to increase IL-10 expression in alveolar macrophages. Lipopolysaccharide (LPS)-stimulated alveolar macrophages co-cultured with human umbilical mesenchymal stem cells (HUMSC) secreted high levels of IL-10. HUMSC co-cultured with alveolar macrophages expressed high STC-1 levels and increased PI3K, AKT and mTOR phosphorylation after LPS activation in alveolar macrophages. STC-1 knockdown in HUMSC decreased the phosphorylation of PI3K, AKT and mTOR and suppressed IL-10 expression in alveolar macrophages. Rapamycin (an mTOR inhibitor) reduced IL-10 secretion in alveolar macrophages. These results, together with our previous study and others, indicate that the PI3K/AKT/mTOR pathway is involved in the regulation of IL-10 production by STC-1 secreted by HUMSC in alveolar macrophages.

Prolonged and intensive medication use are associated with the obesity paradox after percutaneous coronary intervention: a systematic review and meta-analysis of 12 studies.

BACKGROUND: Obesity paradox is defined as the unexpected decrease in the total number of death which has been observed among patients who are overweight and obese compared to patients with normal weight after undergoing revascularization by percutaneous coronary intervention (PCI). Despite of so many recent studies which showed the existence of this phenomenon, prolonged and intensive medication use were only suggested to be among the reasons responsible for this 'obesity paradox' but it was never confirmed whether this hypothesis should really be considered true or not. Therefore, this study aimed to investigate whether prolonged and intensive medication use were associated with this obesity paradox after PCI. METHODS: Medline, PubMed, EMBASE and the Cochrane Library were searched for studies showing the existence of this 'obesity paradox' in patients who underwent coronary revascularization by PCI and only articles comprising of medication use among the patients analyzed were considered relevant for this research. Medication use among the different subgroups of patients was calculated. Mortality was considered as the clinical endpoint in this study. Risk Ratio (RR) with 95 % Confidence Interval (CI) was used to express the pooled effect on discontinuous variables and the pooled analyses were performed with RevMan 5.3. RESULTS: Twelve studies consisting of a total number of 91,582 patients was included in this meta-analysis. An intensive medication use after the hospital discharge and during the follow up period after PCI was observed in the subgroup of obese patients, followed by the overweight patients and the normal weight patients respectively. Our results showed that the short-term (30 days) mortality in overweight and obese patients was significantly lower compared to the normal weight patients with RR: 0.72; 95 % CI: 0.56-0.92, p = 0.008 and RR: 0.47, 95 % CI: 0.34-0.65; p < 0.00001 respectively. The long-term (≥ one year) mortality was also significantly lower in the overweight and the obese groups with RR: 0.74, 95 % CI: 0.67-0.82; p < 0.00001 and RR: 0.63, 95 % CI: 0.55-0.72; p < 0.00001 respectively. CONCLUSION: Our study has confirmed to some extent, that prolonged and intensive use of medications which were more prominent in patients who were overweight and obese during the follow up period, might apparently be among the reasons responsible for this obesity paradox after PCI.

The MK2/HuR signaling pathway regulates TNF-α-induced ICAM-1 expression by promoting the stabilization of ICAM-1 mRNA.

BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by acute lung inflammation. Intercellular adhesion molecule-1 (ICAM-1) and interleukin-8 (IL-8) play an important role in the development of these diseases. Mitogen-activated protein kinase (MAPK) p38/activated protein kinase 2 (MK2) regulates the expression of ICAM-1 and IL-8 in human lung microvascular endothelial cells (HPMECs) stimulated by tumor necrosis factor-α (TNF-α); however, the underlying molecular mechanism remains unclear. Here, we show that human antigen R (HuR), an RNA binding protein which binds preferentially to AU-rich elements (AREs) and stabilizes mRNAs, regulates TNF-α-induced ICAM-1 expression in the MK2/HuR signaling pathway. METHOD: MK2 and HuR were silenced respectively in HPMECs and then HPMECs were stimulatied with TNF-α. Nucleo-cytoplasmic shuttling of HuR was detected by subcellular fractionation and confocal microscopy in MK2 knockdown HPMECs. In HuR silencing cells, protein and mRNA levels of ICAM-1 and IL-8 were measured by western blot analysis, ELISA and real-time PCR; mRNA stabilization were measured by real-time PCR after actinomycin D (ActD) blocking transcription. Furthermore, we performed neutrophil adhesion assay to assess the adhering capacity after HuR silencing. RESULTS: MK2 were subjected to a knockdown by interfering RNA, the mRNA and protein levels of HuR in human pulmonary microvascular endothelial cells (HPMECs) were not affected. However, after the stimulation of TNF-α, silencing MK2 inhibited HuR accumulation to cytoplasm from nucleus in HPMECs. Consequently, knockdown of HuR by RNA interference in HPMECs, there was reduction in the stability of ICAM-1 mRNA and ICAM-1 protein level. This event was accompanied by a decrease in the adhesion of neutrophils towards HPMECs. Nevertheless, HuR silencing had no effect on the mRNA and protein levels of IL-8. CONCLUSION: These results indicate that MK2 post-transcriptionally regulates TNF-α-induced ICAM-1 expression by altering the cytoplasmic localization of HuR in HPMECs.

Brucella infection combined with Nocardia infection: A case report and literature review.

Human brucellosis is an infectious disease caused by Brucella and is often misdiagnosed for atypical manifestations including fever of unknown origin, headache, weakness, among else. Nocardiosis is a zoonotic disease caused by the genus Nocardia, which usually spreads through the respiratory tract, skin, and digestive tract. Limited research has documented cases of co-infection involving both Brucella and Nocardia pathogens in patients. A 55-year-old male was admitted to our hospital with intermittent high-grade fever. Following sputum and blood cultures, as well as other laboratory examinations, the patient was diagnosed with concurrent brucellosis and nocardiosis. According to recommendations of previous studies and reports, the patient was successively treated with levofloxacin, doxycycline, piperacillin sodium and sulbactam sodium, trimethoprim-sulfamethoxazole, rifampicin, and tigecycline, after which the patient recovered and was discharged. Brucella and Nocardia are both opportunistic pathogens and simultaneous infection of Brucella and Nocardia is relatively rare. If patients continue to experience persistent fever despite receiving empirical antibiotic therapy, it becomes necessary to conduct examinations to identify potential atypical pathogens, including Brucella and Nocardia. Sputum staining, sputum culture, and blood culture are critical auxiliary examinations during clinical practice. The treatment plan should be selected based on guidelines and the individual patient's condition. Regular reevaluation should be conducted, and antimicrobial agents should be adjusted accordingly.

Immunogenic cell death inducers for cancer therapy: An emerging focus on natural products.

BACKGROUND: Immunogenic cell death (ICD) is a specific form of regulated cell death induced by a variety of stressors. During ICD, the dying cancer cells release damage-associated molecular patterns (DAMPs), which promote dendritic cell maturation and tumor antigen presentation, subsequently triggering a T-cell-mediated anti-tumor immune response. In recent years, a growing number of studies have demonstrated the potential of natural products to induce ICD and enhance tumor cell immunogenicity. Moreover, there is an increasing interest in identifying new ICD inducers from natural products. PURPOSE: This study aimed to emphasize the potential of natural products and their derivatives as ICD inducers to promote research on using natural products in cancer therapy and provide ideas for future novel immunotherapies based on ICD induction. METHOD: This review included a thorough search of the PubMed, Web of Science, Scopus, and Google Scholar databases to identify natural products with ICD-inducing capabilities. A comprehensive search for clinical trials on natural ICD inducers was also conducted using ClinicalTrials.gov, as well as the approved patents using the Espacenet and CNKI Patent Database. RESULTS: Natural compounds that induce ICD can be categorized into several groups, such as polyphenols, flavonoids, terpenoids, and alkaloids. Natural products can induce the release of DAMPs by triggering endoplasmic reticulum stress, activation of autophagy-related pathways, and reactive oxygen species generation, etc. Ultimately, they activate anti-tumor immune response and improve the efficacy of cancer treatments. CONCLUSION: A growing number of ICD inducers from natural products with promising anti-cancer potential have been identified. The detailed information presented in this review will contribute to the further development of natural ICD inducers and cancer treatment strategies based on ICD-induced responses.

MiR-3074-5p Regulates Trophoblasts Function via EIF2S1/GDF15 Pathway in Recurrent Miscarriage.

Dysfunction of extravillous trophoblasts (EVTs) might cause early pregnancy failure by interfering with embryo implantation and/or placentation. We previously reported that the villus miR-3074-5p expression level was increased, whereas the peripheral level of GDF15, a predict target gene of miR-3074-5p, was decreased in recurrent miscarriages (RM) patients, and miR-3074-5p could enhance apoptosis but reduce invasion of human extravillous trophoblast cells (EVTs). The aim of this study was to further explore roles of miR-3074-5p/GDF15 pathway in regulation of EVTs function. It was validated that GDF15 was not the direct target of miR-3074-5p, whereas EIF2S1, an upstream regulator of GDF15 maturation and secretion, was the direct target of miR-3074-5p. The villus expression levels of GDF15 and EIF2S1 were significantly decreased in RM patients. Knockdown of GDF15 expression presented inhibitory effects on proliferation, migration, and invasion of HTR8/SVneo cells. Up-regulated miR-3074-5p expression led to the significant decreased GDF15 expression in HTR8/SVneo cells, and this effect could be efficiently reversed by the overexpression of EIF2S1. Meanwhile, the suppressive effects of miR-3074-5p on proliferation, migration, and invasion of HTR8/SVneo cells could be intercepted by the treatment of recombinant human GDF15 protein. Collectively, these data suggested that miR-3074-5p could reduce GDF15 production via targeting inhibition of EIF2S1 expression, and the deficiency in GDF15 function might lead to the early pregnancy loss by attenuating proliferation and invasion of EVTs.

Increased miR-3074-5p expression promotes M1 polarization and pyroptosis of macrophages via ERα/NLRP3 pathway and induces adverse pregnancy outcomes in mice.

Decidual macrophages (dMϕs) play critical roles in regulation of immune-microhomeostasis at maternal-fetal interface during pregnancy, but the underlying molecular mechanisms are still unclear. In this study, it was found that litter size and fetal weight were significantly reduced, whereas the rate of embryo resorption was increased in miR-3074-5p knock-in (3074-KI) pregnant mice, compared to that of wild-type (WT) pregnant mice. Plasma levels of pro-inflammatory cytokines in 3074-KI pregnant mice were also significantly elevated compared to WT pregnant mice at GD7.5. The quantity of M1-Mϕs in uterine tissues of 3074-KI pregnant mice was significantly increased compared to WT pregnant mice at GD13.5. Estrogen receptor-α (ERα) was validated to be a target of miR-3074-5p. Either miR-3074-5p overexpression or ERα knockdown promoted transcriptional activity of NF-κB/p65, induced M1-polarization and pyroptosis of THP1-derived Mϕs, accompanied with increased intracellular levels of cleaved Caspase-1, cleaved IL-1ß, NLRP3, cleaved GSDMD and ASC aggregation. Furthermore, ERα could not only bind to NLRP3 or ASC directly, but also inhibit the interaction between NLRP3 and ASC. The endometrial miR-3074-5p expression level at the middle secretory stage of repeated implantation failure (RIF) patients was significantly decreased compared to that of control fertile women. These data indicated that miR-3074-5p could promote M1 polarization and pyroptosis of Mϕs via activation of NLRP3 inflammasome by targeting ERα, and the dysregulation of miR-3074-5p expression in dMϕs might damage the embryo implantation and placentation by interfering with inflammatory microenvironment at the maternal-fetal interface during early pregnancy.

Advancements in autologous stem cell transplantation for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease marked by comparatively focal dopaminergic neuron degeneration in the substantia nigra of the midbrain and dopamine loss in the striatum, which causes motor and non-motor symptoms. Currently, pharmacological therapy and deep brain stimulation(DBS) are the primary treatment modalities for PD in clinical practice. While these approaches offer temporary symptom control, they do not address the underlying neurodegenerative process, and complications often arise. Stem cell replacement therapy is anticipated to prevent further progression of the disease due to its regenerative capacity, and considering the cost of immunosuppression and the potential immune dysfunctions, autologous stem cell transplantation holds promise as a significant method against allogeneic one to treat Parkinson's disease. In this review, the safety concerns surrounding tumorigenicity and complications associated with transplantation are discussed, along with methods utilized to evaluate the efficacy of such procedures. Subsequently, we summarize the preclinical and clinical studies involving autologous stem cell transplantation for PD, and finally talk about the benefits of autologous stem cell transplantation against allogeneic transplants.

[Pathogenesis and staging treatment for non-specific low back pain based on the meridian sinew theory].

Based on the physiological and pathological characteristics of meridian sinew theory, the staging treatment of non-specific low back pain (NLBP) is explored to provide the reference of clinical practice. The twelve meridian sinews of the human body communicate with the bones and joints of the whole body, which governs the movement, body protection and defense, and meridian regulation. Physiologically, the meridian sinew maintains the functions of the lumbar region. In pathology, the meridian sinew may encounter stasis and pain, contraction and spasm or "transverse collateral" formation. According to the pathological staging of meridian sinew disorders, the progress of NLBP is divided into 3 phases and the corresponding treatments are provided. Mild stimulation and rapid analgesia is suggested to promote tissue repair at the early phase; muscle spasm is relieved to adjust muscular status at the middle phase; and the "cord-like" muscle foci is removed at the later phase of the disease.

Calpain inhibitor MDL28170 alleviates cerebral ischemia­reperfusion injury by suppressing inflammation and autophagy in a rat model of cardiac arrest.

Cerebral ischemia-reperfusion injury (CIRI) is associated with a poor neurological prognosis in patients who have experienced cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). The aim of the current study was to investigate the potential role of a calpain inhibitor in CIRI using a rat model of CA. CA was induced in adult male Sprague-Dawley rats, and MDL28170 (a calpain inhibitor) was administered to the rats within 30 min after the return of spontaneous circulation. Differences between groups were evaluated by measuring survival rate, CPR duration and neurological deficit score. Hematoxylin-eosin staining and Nissl staining were performed to assess cerebral injury, and microstructure and autophagy were assessed by transmission electron microscopy. The levels of calpain-1, calpain-2, calpastatin, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, P62, beclin-1 and LC3 in the brain tissues were determined using western blotting and double immunofluorescence staining. There was no significant difference in CPR duration or survival rate among the groups. At 24 h after CPR, the CA group demonstrated damaged tissue morphology; decreased neurological deficit scores, and P62 expression; and upregulated calpain-2, IL-1ßp17, TNF-α, beclin-1 and LC3 levels in the cortex. However, MDL28170 improved neuronal function and suppressed inflammation and autophagy by inhibiting calpain-2 level, but there were no differences in the calpain-1 and calpastatin levels. These results suggest that calpain-2, inflammation and autophagy are involved in CA-induced CIRI. MDL28170 inhibited calpain-2 expression, inflammation and autophagy, which suggests its potential efficacy in treating post-CA nerve damage.

MK2 posttranscriptionally regulates TNF-α-induced expression of ICAM-1 and IL-8 via tristetraprolin in human pulmonary microvascular endothelial cells.

Tristetraprolin (TTP), a substrate of p38 mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), is an RNA-binding protein that binds to AU-rich elements (AREs) in the 3'-untranslated region (3'-UTR) of its target mRNAs and accelerates mRNA degradation. A previous study by our group showed that MK2 regulates tumor necrosis factor-α (TNF-α)-induced expression of intercellular adhesion molecule-1 (ICAM-1) and interleukin-8 (IL-8) in human lung microvascular endothelial cells; however, the downstream protein of MK2 remains unknown. Interestingly, both ICAM-1 and IL-8 have AREs in the 3'-UTR of their mRNAs. In the present study, we performed experiments to determine whether MK2 regulates TNF-α-induced expression of ICAM-1 and IL-8 via TTP in human pulmonary microvascular endothelial cells (HPMECs). The study revealed that MK2 silencing significantly reduced the half-lives of ICAM-1 and IL-8 mRNAs in TNF-α-stimulated HPMECs. TTP phosphorylation levels were decreased in MK2-silenced cells. TTP silencing led to mRNA stabilization of ICAM-1 and IL-8 and upregulation of protein production following TNF-α stimulation. These results, together with our previous study and others, suggest that MK2, in HPMECs, regulates TNF-α-induced expression of ICAM-1 and IL-8 via TTP at the mRNA decay level.

SEC5 is involved in M2 polarization of macrophages via the STAT6 pathway, and its dysfunction in decidual macrophages is associated with recurrent spontaneous abortion.

Decidual macrophages (dMϕs) play critical roles in the establishment of microhomeostasis at the maternal-fetal interface during pregnancy. Impaired macrophage polarization during early pregnancy is associated with recurrent spontaneous abortion (RSA). In the present study, the SEC5 expression level was found to be significantly decreased in primary dMϕs of patients with RSA, and downregulation of SEC5 expression inhibited M2 polarization and STAT6 phosphorylation, whereas SEC5 overexpression in the Mϕs promoted M2 polarization and STAT6 phosphorylation in vitro. We subsequently found that SEC5 interacted with STAT6 in THP-1-derived Mϕs. The abundance of phosphorylated STAT6 (pSTAT6) protein was obviously increased, with a predominant distribution in the nucleus, after M2 polarization of Mϕs, and SEC5 protein was colocalized with pSTAT6. Moreover, a significantly reduced pSTAT6 expression level was observed in the dMϕs of patients with RSA. M2 polarization of Mϕs showed a stimulatory effect on the proliferation and invasion of human extravillous trophoblasts (EVTs) in vitro, and downregulation of SEC5 expression in Mϕs effectively reversed this effect. In a mouse model of LPS-induced early pregnancy loss, the uterine SEC5 expression level and the number of M2-Mϕs at the maternal-fetal interface were significantly reduced. More interestingly, heterozygous SEC5-deficient (SEC5-/+) pregnant mice were more sensitive to LPS-induced pregnancy loss. Taken together, these data indicate that SEC5 participates in the regulation of M2 polarization of Mϕs by interacting with STAT6 and that decreased SEC5 expression inhibits the M2 polarization of dMϕs and results in early pregnancy loss by interfering with the physical activities of EVTs and immunotolerance at the maternal-fetal interface.

Effect of glucocorticoids on mortality in patients with acute respiratory distress syndrome: A meta-analysis.

To date, the efficacy of glucocorticoid therapy to reduce mortality in patients with acute respiratory distress syndrome (ARDS) has remained controversial among the studies available. The present meta-analysis study aimed to further clarify the impact of glucocorticoid therapy on mortality in patients with ARDS by performing a pooled analysis of the previous data. The PubMed, Chinese Knowledge Infrastructure, Wanfang and Cochrane trials databases were searched for relevant studies published between 1966 and 2016. Randomized controlled trials (RCTs) that included the use of glucocorticoids in patients with ARDS and had reported on mortality were included. Odds ratios (OR) and 95% confidence intervals (CI) for mortality were calculated. A total of 10 RCTs were included in the meta-analysis. Of these, 4 studies used high-dose glucocorticoid therapy, while 6 used low-dose glucocorticoid therapy. In the pooled analysis, glucocorticoids were indicated to significantly reduce ARDS-associated mortality (OR=0.64, 95% CI: 0.48-0.85, P=0.002). Further subgroup analysis indicated the following: i) Long-term low-dose glucocorticoid therapy reduced ARDS-associated mortality compared with that in the control group (OR=0.60, 95% CI: 0.44-0.82, P=0.001), whereas high-dose short-term glucocorticoid therapy did not reduce mortality (OR=0.82, 95% CI: 0.43-1.57, P=0.55). ii) Early initiation of glucocorticoid therapy was associated with reduced mortality compared with that in the control group (OR=0.60, 95% CI: 0.44-0.83, P=0.002); however, late initiation did not reduce mortality (OR=0.36, 95% CI: 0.03-3.76, P=0.39). iii) Therapeutic rather than preventive use of glucocorticoids reduced mortality (OR=0.65, 95% CI: 0.49-0.86, P=0.003). Overall, the present meta-analysis suggests that early initiation of long-term low-dose glucocorticoid therapy reduces mortality of patients with ARDS.

CNOT1 is involved in TTP­mediated ICAM­1 and IL­8 mRNA decay.

Subunit 1 is the scaffold protein of the carbon catabolite repressor protein 4 (CCR4)­negative on TATA (NOT) complex (CNOT1). In our previous study, it was reported that tristetraprolin (TTP) could recruit subunit 7 of the CCR4­NOT complex (CNOT7) to induce the degradation of intercellular adhesion molecule­1 (ICAM­1) and interleukin­8 (IL­8) mRNA in human pulmonary microvascular endothelial cells (HPMECs). It was additionally demonstrated that TTP, CNOT7 and CNOT1 formed a complex in HPMECs. However, whether CNOT1 is involved in TTP­mediated ICAM­1 and IL­8 mRNA decay remains unclear. The present study demonstrated that CNOT1 knockdown improved ICAM­1 and IL­8 mRNA stabilization and protein expression levels. The immunofluorescence results demonstrated that CNOT1, CNOT7 and TTP are co­localized in the cytoplasm. CNOT1 silencing abolished CNOT7 and TTP coimmunoprecipitation. However, CNOT7 silencing did not influence CNOT1 and TTP coimmunoprecipitation, and TTP silencing additionally did not influence CNOT1 and CNOT7 coimmunoprecipitation. These results together with the authors' previous study, have identified that CNOT1 provides a platform for the recruitment of TTP and CNOT7, and is involved in TTP­mediated ICAM­1 and IL­8 mRNA decay.

Head to head comparison of Prasugrel versus Ticagrelor in patients with acute coronary syndrome: a systematic review and meta-analysis of randomized trials.

BACKGROUND: Prasugrel and Ticagrelor are emerging antiplatelet drugs that might have the potential to replace currently used antiplatelet agents. Previous analyses comparing prasugrel with ticagrelor mainly focused on an indirect comparison whereas direct comparison was reported only in a few recently published trials. We aimed to systematically carry out a head to head comparison of the adverse clinical outcomes which were associated with prasugrel versus ticagrelor in patients with acute coronary syndrome (ACS). METHODS: Studies comparing prasugrel with ticagrelor (head to head comparison) were searched from online databases. Adverse cardiovascular outcomes were considered as the primary endpoints whereas bleeding outcomes were considered as the secondary endpoints in this analysis. The latest version of the RevMan software was used to carry out subgroup analyses whereby odds ratios (OR) with 95% confidence intervals (CI) and the calculated probability (P) were generated. RESULTS: Four studies with a total number of 563 patients (2012 - 2016) were included (282 patients were treated with prasugrel and 281 patients were treated with ticagrelor). Results of this analysis did not show any significant difference in mortality between prasugrel and ticagrelor with OR: 1.52, 95% CI: 0.42 - 5.45; P = 0.52. In addition, myocardial infarction, major adverse cardiac events, stroke and stent thrombosis were also not significantly different with OR: 0.59, 95% CI: 0.08 - 4.58; P = 0.62, OR: 0.91, 95% CI: 0.37 - 2.21; P = 0.83, OR: 0.60, 95% CI: 0.08 - 4.58; P = 0.62 and OR: 0.59, 95% CI: 0.08 - 4.58; P = 0.62 respectively. Thrombolysis in myocardial infarction (TIMI) defined minor bleeding, and minimal bleeding were also not significantly different between these two newer antiplatelet agents with OR: 3.11, 95% CI: 0.48 - 19.94; P = 0.23, and OR: 2.39, 95% CI: 0.35 - 16.42; P = 0.38 respectively. Moreover, bleeding defined by the academic research consortium was also similarly manifested with OR: 0.92, 95% CI: 0.39 - 2.13; P = 0.84. CONCLUSION: In patients with ACS, both prasugrel and ticagrelor showed similar adverse cardiovascular outcomes and bleeding events. No significant difference was observed between these two newer antiplatelet agents during this head to head comparison. However, upcoming trials with long term follow up periods might be expected to completely solve this important clinical issue.

PlenoPatch: Patch-Based Plenoptic Image Manipulation.

Patch-based image synthesis methods have been successfully applied for various editing tasks on still images, videos and stereo pairs. In this work we extend patch-based synthesis to plenoptic images captured by consumer-level lenselet-based devices for interactive, efficient light field editing. In our method the light field is represented as a set of images captured from different viewpoints. We decompose the central view into different depth layers, and present it to the user for specifying the editing goals. Given an editing task, our method performs patch-based image synthesis on all affected layers of the central view, and then propagates the edits to all other views. Interaction is done through a conventional 2D image editing user interface that is familiar to novice users. Our method correctly handles object boundary occlusion with semi-transparency, thus can generate more realistic results than previous methods. We demonstrate compelling results on a wide range of applications such as hole-filling, object reshuffling and resizing, changing object depth, light field upscaling and parallax magnification.

CAF1-knockout mice are more susceptive to lipopolysaccharide-induced acute lung injury.

The carbon catabolite repressor protein 4 (CCR4)-negative on TATA (NOT) complex includes multiple subunits and is conserved in the eukaryotic cells. The CCR4-NOT complex can regulate gene expression at different levels. Two subunits of the CCR4-NOT complex, CCR4 and CCR4-associated factor 1 (CAF1), possess deadenylase activity. In yeast, the deadenylase activity is mainly provided by the CCR4 subunit; however, the deadenylase activity is provided by both CCR4 and CAF1 in other eukaryotes. A previous study reported that CAF1 but not CCR4 is required for the decay of a reporter mRNA with AU-rich elements. Our previous study showed that CAF1 is involved in the regulation of intercellular adhesion molecule-1 (ICAM-1) and interleukin-8 (IL-8) expression. Both ICAM-1 and IL-8 play crucial roles in acute lung injury. In the present study, we examined the effects of CAF1 deficiency on IL-8 and ICAM-1 expression and acute lung injury in mice. Here we showed that there were no differences between the wild-type and CAF1-knockout mice on phenotypes. The lung histology and protein and mRNA levels of IL-8 and ICAM-1 in unstimulated wild-type mice were comparable to those in unstimulated CAF1-knockout mice. However, lipopolysaccharide stimulation led to more severe lung histological injury and greatly higher IL-8 and ICAM-1 expression in CAF1-knockout mice compared to the wild-type mice. These results, together with our previous study, suggest that CAF1 is involved in the regulation of lipopolysaccharide-stimulated IL-8 and ICAM-1 expression in vivo and affects the progression of acute lung injury.

CNOT7/hCAF1 is involved in ICAM-1 and IL-8 regulation by tristetraprolin.

Tristetraprolin (TTP) is an RNA-binding protein which can bind to the AU-rich elements (AREs) at the 3'-untranslated region (3'-UTR) of target mRNA and promote mRNA deadenylation and degradation. We have shown in a previous study that TTP regulates tumor necrosis factor-α (TNF-α)-induced expression of intercellular adhesion molecule-1 (ICAM-1) and interleukin-8 (IL-8), both of whose mRNAs have AREs in the 3'-UTR, in human pulmonary microvascular endothelial cells (HPMEC) through destabilizing target mRNAs, nevertheless, the mechanism by which TTP promotes mRNA decay remains unclear. Observations have indicated that TTP can interact with CAF1 (CNOT7/hCAF1 in human), a subunit of the CCR4-NOT complex with deadenylase activity. Another study illustrated that TTP can directly bind to CNOT1, the scaffold subunit of the CCR4-NOT complex. The present study showed that TTP bound to the AREs of ICAM-1 and IL-8 mRNAs and was coimmunoprecipitated with intracellular ICAM-1 and IL-8 mRNAs. TTP, CNOT7 and CNOT1 were coimmunoprecipitated in HPMEC. CNOT7 silencing stabilized ICAM-1 and IL-8 mRNAs and increased ICAM-1 and IL-8 production following TNF-α stimulation. These results, together with our previous study, suggest that CNOT7/hCAF1 is involved in ICAM-1 and IL-8 regulation by TTP in HPMEC.

The effect of belief in free will on prejudice.

The current research examined the role of the belief in free will on prejudice across Han Chinese and white samples. Belief in free will refers to the extent to which people believe human beings truly have free will. In Study 1, the beliefs of Han Chinese people in free will were measured, and their social distances from the Tibetan Chinese were used as an index of ethnic prejudice. The results showed that the more that Han Chinese endorsed the belief in free will, the less that they showed prejudice against the Tibetan Chinese. In Study 2, the belief of the Han Chinese in free will was manipulated, and their explicit feelings towards the Uyghur Chinese were used as an indicator of ethnic prejudice. The results showed that the participants in the condition of belief in free will reported less prejudice towards Uyghur Chinese compared to their counterparts in the condition of disbelief in free will. In Study 3, white peoples' belief in free will was manipulated, and their pro-black attitudes were measured as an indirect indicator of racial prejudice. The results showed that, compared to the condition of disbelief in free will, the participants who were primed by a belief in free will reported stronger pro-black attitudes. These three studies suggest that endorsement of the belief in free will can lead to decreased ethnic/racial prejudice compared to denial of the belief in free will. The theoretical and practical implications are discussed.

Tristetraprolin is involved in the glucocorticoid-mediated interleukin 8 repression.

Glucocorticoids have been widely used in various inflammatory disorders, and the transcriptional repression of inflammatory mediators has been considered to be the main mechanism of action. However, a previous study showed that dexamethasone inhibited interleukin 8 (IL-8) expression by promoting IL-8 mRNA decay, which implies a posttranscriptional regulation. Nevertheless, by which mechanism dexamethasone destabilized IL-8 mRNA was unclear. Another study indicated that an RNA-binding protein, tristetraprolin (TTP), could be induced by dexamethasone. TTP can bind to AU-rich elements (ARE) in the 3'-untranslated region of target mRNAs and promotes mRNA degradation. So, we speculated that dexamethasone destabilized IL-8 mRNA by upregulating TTP expression. Here, we report that dexamethasone reduced IL-8 expression through destabilizing IL-8 mRNA in human pulmonary microvascular endothelial cells (HPMECs). Dexamethasone stimulation increased TTP mRNA and protein levels. TTP silencing led to mRNA stabilization and protein upregulation of IL-8. These results provide the evidence that the glucocorticoid, in HPMECs, inhibits IL-8 expression through TTP at the posttranscriptional level.