Rotation Equivariant Proximal Operator for Deep Unfolding Methods in Image Restoration.

The deep unfolding approach has attracted significant attention in computer vision tasks, which well connects conventional image processing modeling manners with more recent deep learning techniques. Specifically, by establishing a direct correspondence between algorithm operators at each implementation step and network modules within each layer, one can rationally construct an almost "white box" network architecture with high interpretability. In this architecture, only the predefined component of the proximal operator, known as a proximal network, needs manual configuration, enabling the network to automatically extract intrinsic image priors in a data-driven manner. In current deep unfolding methods, such a proximal network is generally designed as a CNN architecture, whose necessity has been proven by a recent theory. That is, CNN structure substantially delivers the translational symmetry image prior, which is the most universally possessed structural prior across various types of images. However, standard CNN-based proximal networks have essential limitations in capturing the rotation symmetry prior, another universal structural prior underlying general images. This leaves a large room for further performance improvement in deep unfolding approaches. To address this issue, this study makes efforts to suggest a high-accuracy rotation equivariant proximal network that effectively embeds rotation symmetry priors into the deep unfolding framework. Especially, we deduce, for the first time, the theoretical equivariant error for such a designed proximal network with arbitrary layers under arbitrary rotation degrees. This analysis should be the most refined theoretical conclusion for such error evaluation to date and is also indispensable for supporting the rationale behind such networks with intrinsic interpretability requirements. Through experimental validation on different vision tasks, including blind image super-resolution, medical image reconstruction, and image de-raining, the proposed method is validated to be capable of directly replacing the proximal network in current deep unfolding architecture and readily enhancing their state-of-the-art performance. This indicates its potential usability in general vision tasks.

Promising Roles of Exosomal microRNAs in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the loss of immune tolerance. Lupus nephritis (LN) is still a major cause of the morbidity and mortality of SLE. In clinical practice, diagnosis, and therapy of SLE is complicated and challenging due to lack of ideal biomarkers. Exosomes could be detected from numerous kinds of biological fluids and their specific contents are considered as hallmarks of autoimmune diseases. The exosomal miRNA profiles of SLE/LN patients significantly differ from those of the healthy controls making them as attractive biomarkers for renal injury. Exosomes are considered as optimal delivery vehicles owing to their higher stable, minimal toxicity, lower immunogenicity features and specific target effects. Endogenous miRNAs can be functionally transferred by exosomes from donor cells to recipient cells, displaying their immunomodulatory effects. In addition, it has been confirmed that exosomal miRNAs could directly interact with Toll-like receptors (TLRs) signaling pathways to regulate NF-κB activation and the secretion of inflammatory cytokines. The present Review mainly focuses on the immunomodulatory effects of exosomal-miRNAs, the complex interplay between exosomes, miRNAs and TLR signaling pathways, and how the exosomal-miRNAs can become non-invasive diagnostic molecules and potential therapeutic strategies for the management of SLE.

KDM6 Demethylases and Their Roles in Human Cancers.

Cancer therapy is moving beyond traditional chemotherapy to include epigenetic approaches. KDM6 demethylases are dynamic regulation of gene expression by histone demethylation in response to diverse stimuli, and thus their dysregulation has been observed in various cancers. In this review, we first briefly introduce structural features of KDM6 subfamily, and then discuss the regulation of KDM6, which involves the coordinated control between cellular metabolism (intrinsic regulators) and tumor microenvironment (extrinsic stimuli). We further describe the aberrant functions of KDM6 in human cancers, acting as either a tumor suppressor or an oncoprotein in a context-dependent manner. Finally, we propose potential therapy of KDM6 enzymes based on their structural features, epigenetics, and immunomodulatory mechanisms, providing novel insights for prevention and treatment of cancers.

Sodium Butyrate Ameliorates Intestinal Injury and Improves Survival in a Rat Model of Cecal Ligation and Puncture-Induced Sepsis.

Sepsis is a life-threatening condition with a high rate of mortality. Unfortunately, very few therapies can improve outcomes in patients with sepsis. Butyrate, which is the most potent histone deacetylase (HDAC) inhibitor among short-chain fatty acids, exerts anti-inflammatory effects in a variety of inflammatory diseases. Butyrate might thus be valuable in the treatment of sepsis, in which inhibition of overwhelming cytokine release is vitally important. Sepsis was induced in 7- to 8-week-old Sprague-Dawley rats by cecal ligation and puncture (CLP) with a 21-g double-puncture technique. Rats received an intravenous injection of normal saline (vehicle) or sodium butyrate (200 mg/kg) after CLP and were sacrificed 12 h later. Hematoxylin and eosin staining was performed to observe the intestinal mucosal morphology. RT-PCR and ELISA were used to determine the intestinal inflammatory response in vivo. Intestinal permeability was evaluated by measuring fluorescein isothiocyanate dextran (FD-4) absorption in vivo, and tight junction protein expression was examined by western blot. NF-κB p65 activities were assessed by western blot and immunohistochemistry. Sodium butyrate treatment improved the survival rate of CLP rats and alleviated sepsis-induced intestinal mucosal injury. Proinflammatory cytokine expression was lower in butyrate-treated rats than in the vehicle group. FD-4 leakage from the intestinal tract was reduced, and the expression levels of the tight junction proteins claudin-1 and ZO-1 were also restored in rats that received sodium butyrate treatment. These effects were associated with less NF-κB p65 nuclear translocation, whereas the expression of Iκ-Bα was not affected or even increased. Sodium butyrate mitigates the inflammatory response and maintains intestinal barrier function in polymicrobial sepsis partly through inhibition of NF-κB activation and may serve as a novel therapy for sepsis.

[Effect of vitamin D3 on the severity and prognosis of patients with sepsis: a prospective randomized double-blind placebo study].

OBJECTIVE: To observe the relationship between vitamin D3 and the severity as well as prognosis in patients with sepsis, and to explore whether exogenous vitamin D3 can improve the prognosis in patients with sepsis. METHODS: A prospective randomized double-blind placebo study was conducted. Fifty-seven patients with sepsis admitted to intensive care unit (ICU) of Shengjing Hospital Affiliated to China Medical University from March to November in 2015 were enrolled. Twenty patients with systemic inflammatory response syndrome (SIRS) and 20 healthy volunteers with normal physical examination as control were enrolled during the same time. Patients with sepsis were divided into general sepsis group and severe sepsis group (including septic shock) according to the criteria for the diagnosis of severe sepsis and septic shock in 2012. According to the diagnostic criteria established by the American Endocrine Society, and on the basis of 25-hydroxy vitamin D3 [25(OH)D3], the sepsis patients with deficiency [25(OH)D3 20-30 µg/L] or insufficiency [25(OH)D3 < 20 µg/L] of vitamin D were divided into D3 treatment group (supplemented 300 kU vitamin D3) and placebo group (injected 1 mL physiological saline). 28th day was set as the end point, and the patients with sepsis were divided into survival group and death group. The levels of serum 25(OH)D3 in each group were measured by electrochemical luminescence method, and the difference in 25(OH)D3 levels among patients with different severity, gender, and age were recorded. Procalcitonin (PCT), C-reactive protein (CRP), blood routine, liver and kidney function, electrolytes and arterial blood gas analysis, acute physiology and chronic health evaluation II (APACHE II) and sequential organ failure score (SOFA), duration of mechanical ventilation, and length of ICU stay of patients with sepsis were observed. Multivariate Cox proportional hazard regression analysis was used to analyze the risk factors of prognosis in patients with sepsis. RESULTS: (1) In 57 patients with sepsis, there were 15 patients in general sepsis group, and 42 in severe sepsis group; 29 in D3 treatment group, and 28 in the placebo group; 8 patients died within 28 days with mortality rate of 14.04%. (2) The levels of serum 25(OH)D3 in sepsis group and SIRS group were significantly lower than those in healthy control group [µg/L: 3.92 (< 3.00, 11.22), 6.99 (3.51, 9.77) vs. 17.25 (13.48, 22.50), both P < 0.01], but there was no significant difference in the serum 25(OH)D3 level between sepsis group and SIRS group as well as patients with different degrees of sepsis. The serum 25(OH)D3 level in female patients with sepsis (n = 24) was significantly lower than that in male (n = 33), and the difference was statistically significant [µg/L: <3.00 (<3.00, 3.87) vs. 11.96 (5.14, 17.29), Z = -4.020, P = 0.000]. There was no significant difference in serum 25(OH)D3 level between the young (age <60 years old, n = 30) and the old (age ≥ 60 years old, n = 27) patients with sepsis [µg/L: 4.54 (<3.00, 9.88) vs. 3.00 (<3.00, 15.08), Z = -0.601, P = 0.548]. (3) In patients with sepsis, there was no significant difference in the duration of mechanical ventilation [hours: 41.00 (7.50, 82.50) vs. 67.00 (4.75, 127.75)], length of ICU stay (days: 5.48±4.08 vs. 6.68±4.87) and 28-day mortality (10.34% vs. 17.86%) between D3 treatment group and placebo group (all P > 0.05). It was shown by Kaplan-Meier survival curve analysis that there was no significance in 28-day accumulated survived rate between the two groups [log-rank test: χ 2 = 0.222, P = 0.638]. It was shown by multivariate Cox regression analysis that APACHE II score [relative risk (RR) = 8.487, 95% confidence interval (95%CI) = 1.506-47.835, P = 0.015] and 25(OH)D3 < 20 µg/L (RR = 0.088, 95%CI = 0.013-0.592, P = 0.012) were the risk factors of prognosis in patients with sepsis. CONCLUSIONS: The serum 25(OH)D3 level in ICU patients with sepsis was lower than that in healthy people, but there was no significant difference between patients with sepsis and SIRS. The serum 25(OH)D3 level in sepsis patients was related with gender, and the level of the female was lower than that of the male, but was not related with age. Exogenous vitamin D3 supplementation cannot improve the prognosis of ICU patients with sepsis. APACHE II score and 25(OH)D3 < 20 µg/L were risk factors for the prognosis in ICU patients with sepsis.

Alpha-lipoic acid exerts anti-inflammatory effects on lipopolysaccharide-stimulated rat mesangial cells via inhibition of nuclear factor kappa B (NF-κB) signaling pathway.

Sepsis is often initiated by invasive infection, characterized by overwhelming induction of pro-inflammatory cytokines. The incidence and mortality of sepsis and the associated development of acute kidney injury (AKI) remain high, and lines of research into potential treatments are needed. This study was conducted to investigate effects of alpha-lipoic acid (ALA) on septic AKI in vitro. ALA of 200 or 400 µM was used to pretreat rat HBZY-1 mesangial cells before commencement of 1 µg/mL lipopolysaccharide (LPS). Our data indicated that ALA pretreatment reduced LPS-stimulated release of inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1 beta (IL-1ß), as well as IL-6, in HBZY-1 cell supernatant. Moreover, LPS-induced expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) was inhibited by ALA pretreatment, and consequently, the secretion levels of their respective enzymatic products prostaglandin E2 (PGE2) and nitric oxide (NO) were significantly decreased. LPS-enhanced phosphorylation of nuclear factor kappa B (NF-κB) inhibitor alpha (IκBα) and IκB kinase alpha/beta (IKKα/ß) and nuclear translocation of NF-κB subunit p65 in HBZY-1 cells were inhibited by ALA pretreatment. Additionally, the NF-κB inhibitor N-acetylcysteine (NAC) exerted similar inhibitory effects as ALA on COX-2 and iNOS expression. In summary, our study demonstrates that ALA mitigates LPS-induced inflammatory responses in rat mesangial cells probably via inhibition of NF-κB signaling pathway, suggesting a therapeutic potential of ALA in AKI related to sepsis.

[The effects of preconditioning and postconditioning with isoflurane on focal cerebral ischemi/reperfusion injury in rats].

OBJECTIVE: To investigate the effects of preconditioning and postconditioning with isoflurane on pro-inflammatory cytokines and lipid peroxidation in focal cerebral ischemic/reperfusion (I/R) injury in rats. METHODS: Thirty-two Sprague-Dawley (SD) rats were randomly divided into four groups: control group, model group, isoflurane preconditioning group and isoflurane postconditioning group, with 8 rats in each group. Rats in control group did not receive any challenge. In rats of model group right middle cerebral artery occlusion (MCAO) was conducted for 90 minutes. Rats in isoflurane preconditioning group received 2% isoflurane exposure for 30 minutes 24 hours before MCAO for 90 minutes. Rats in isoflurane postconditioning group were given 60-minute 2% isoflurane exposure after reperfusion of right MCAO. Twenty-four hours after the procedure, all rats were anesthetized with isoflurane, and blood sample taken from the heart was centrifuged, and the pro-inflammatory cytokines, including interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), and lipid peroxidation products such as malonaldehyde (MDA) and superoxide dismutase (SOD) were determined. The mRNA and protein expression levels of matrix metalloproteinase (MMP-2, MMP-9), tight junction protein Calaudin-5 and Occludin were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western Blot. RESULTS: Compared with control group, serum levels of IL-1ß, TNF-α and MDA were elevated and activity of SOD decreased in rats of model group (IL-1ß: 76.81±11.14 ng/L vs. 52.43 ± 8.86 ng/L, TNF-α: 64.93 ± 10.81 ng/L vs. 33.64 ± 7.94 ng/L, MDA: 8.63 ± 1.42 µmol/L vs. 4.14 ± 0.98 µmol/L, SOD: 0.95 ± 0.21 U/L vs. 2.36 ± 0.80 U/L, all P<0.05). After isoflurane preconditioning and postconditioning, compared with model group, the levels of IL-1ß, TNF-α and MDA were lowered, while activity of SOD was increased (IL-1ß: 54.37 ± 9.06 ng/L, 56.82 ± 8.67 ng/L vs. 76.81 ± 11.14 ng/L, TNF-α: 43.72 ± 6.16 ng/L, 39.49 ± 9.34 ng/L vs. 64.93 ± 10.81 ng/L, MDA: 5.65 ± 0.83 µmol/L, 5.82 ± 0.78 µmol/L vs. 8.63 ± 1.42 µmol/L, SOD: 1.64 ± 0.47 U/L, 1.71 ± 0.52 U/L vs. 0.95 ± 0.21 U/L, all P<0.05). Focal cerebral I/R injury could lead to an increased expression of MMP accompanied with a decreased expression of tight junction protein. Compared with model group, after isoflurane preconditioning and postconditioning, it was found that there were decreased mRNA and protein expression of MMP-2 and MMP-9 (MMP-2 mRNA: 1.25 ± 0.08, 1.32 ± 0.12 vs. 2.48 ± 0.26, MMP-2 protein: 1.56 ± 0.09, 1.50 ± 0.08 vs. 2.12 ± 0.11; MMP-9 mRNA: 1.26 ± 0.13, 1.20 ± 0.12 vs. 2.74 ± 0.28, MMP-9 protein: 1.53 ± 0.04, 1.51 ± 0.05 vs. 2.23 ± 0.09, all P<0.05) and increased levels of Calaudin-5 and Occludin (Claudin-5 mRNA: 0.40 ± 0.08, 0.38 ± 0.06 vs. 0.28 ± 0.03, Claudin-5 protein: 0.80 ± 0.06, 0.81 ± 0.07 vs. 0.39 ± 0.02; Occludin mRNA: 0.54 ± 0.07, 0.50 ± 0.08 vs. 0.26 ± 0.06, Occludin protein: 0.64 ± 0.06, 0.69 ± 0.05 vs. 0.49 ± 0.02, all P<0.05). CONCLUSIONS: Preconditioning and postconditioning with isoflurane can lower the levels of pro-inflammatory cytokines and the degree of lipid peroxidation, and lower the hydrolytic activity of MMP to the tight junction protein in cerebral tissue, thereby decrease the loss of tight junction protein and alleviate I/R injury.

[The occurrence of hypophosphatemia and its prognostic value in intensive care unit patients].

OBJECTIVE: To investigate the occurrence of hypophosphatemia in intensive care unit (ICU) patients, and to study the influence of different levels of phosphorus on the prognosis of patients. METHODS: One hundred and forty-seven patients admitted to Shengjing Hospital during April to November in 2010 were enrolled. The serum phosphorous level was measured consecutively, and the incidence of hypophosphatemia was observed. Acute physiology and chronic health evaluation II (APACHE II ) score, length of ICU-stay, the main laboratory findings and mortality were compared among patients with different serum phosphate levels. Receiver operating characteristic curve (ROC curve) was plotted according to the serum phosphate level and the survivability of patients to study the prognostic value of serum phosphate level in the ICU patients. RESULT: A large number of ICU patients (77.6%) had developed hypophosphatemia, mild in 21, midrange in 70, and marked in 23, amounting to 63.3% of patients suffering from medium and marked hypophosphatemia. The APACHE II score, duration of artificial ventilation (days), length of ICU-stay (days) as well as mortality rate were higher in hypophosphatemia patients compared with those of the normal group (APACHE II score: mild 18.2 ± 6.0, midrange 21.4 ± 7.6, marked 25.6 ± 8.8, normal 18.9 ± 8.8; length of artificial ventilation: mild 6.6 ± 5.1, midrange 11.3 ± 9.5, marked 15.7 ± 10.4, normal 6.7 ± 5.9; length of ICU-stay: mild 9.7 ± 6.4, medium 10.6 ± 8.2, marked 18.9 ± 13.1, normal 9.9 ± 7.1; mortality rate: mild 14.3%, medium 25.7%, marked 39.1%, normal 9.1%). The mortality of ICU patients (22.4%) was negatively correlated with the degree of hypophosphatemia (r = -0.225, P = 0.01). The serum phosphate level had a prognostic value when it was less than 0.40 mmol/L, with sensitivity of 78.6%, specificity of 51.5%. CONCLUSIONS: For most of ICU patients, the serum phosphorus is at a relatively low level. ICU patients have multiple risk factors to develop hypophosphatemia and severe hypophosphatemia is a predictor of a poor prognosis.

[The relativity of vascular endothelium growth factor receptor-1 and preeclampsia].

OBJECTIVES: (1) To investigate the levels of the serum soluble endothelial growth factor receptor-1 in women with preeclampsia and compare the difference between the groups of the mild preeclampsia, severe preeclampsia and eclampsia. For more, to analyze the relativity between the levels of the serum soluble vascular growth factor receptor-1 and preeclampsia. (2) To detect the expression of the membrane-bound VEGFR-1 protein in the placenta tissue of the women with preeclampsia and compare the difference between the groups of the mild preeclampsia, severe preeclampsia and eclampsia, Then to analyze the relativity between the expression of the membrane-bound endothelial growth factor receptor-1 and preeclampsia. METHODS: (1) The serum levels of sVEGFR-1 in 10 women with mild preeclampsia, 10 women with severe preeclampsia, 10 women with eclampsia, 10 women without preeclampsia were detected by the quantitative sandwich enzyme immunoassay technique. (2) Immunohistochemistry and quantitative analysis were used to detect membrane-bound VEGFR-1 contents and distribution in the placenta tissue. RESULTS: (1) The results showed that the serum sVEGFR-1 levels of all preeclampsia groups were relatively higher than those of control group (P < 0.05) and that there were significant differences between the groups of the mild preeclampsia, severe preeclampsia and eclampsia. (2) In placentas, the positive staining was detected predominantly in the membranes of villus syncytiotrophoblast cells, extravillous trophoblast cells, and villus endothelial cells. In fetal membranes, the positive staining was detected predominantly in amnionic endothelial cells. (3) The contents of membrane-bound VEGFR-1 in placenta of preeclampsia groups were relatively lower than that of control group. There were significant differences between membrane-bound VEGFR-1 contents of the mild preeclampsia,severe preeclampsia and eclampsia (P < 0.05). (4) The ratio of the sVEGFR-1 concentration in serum and the membrane-bound VEGFR-1 contents in placenta of preeclampsia groups (sVEGFR-1/ membrane-bound VEGFR-1) was relatively higher than that of control group (P < 0.05) and there were significant differences between the groups of the mild preeclampsia, severe preeclampsia and eclampsia (P < 0.05). CONCLUSIONS: (1) The serum sVEGFR-1 levels of preeclampsia groups were relatively higher than those of control group, the VEGFR-1 may be related to preeclampsia. (2) The contents of membrane-bound VEGFR-1 in placenta of preeclampsia groups were relatively lower than that of control group, the membrane-bound VEGFR-1 may relate to preeclampsia. (3) The ratio of the sVEGFR-1 concentration in serum and the membrane-bound VEGFR-1 contents in placenta of preeclampsia groups (sVEGFR-1/membrane-bound VEGFR-1) was relatively higher than that of control group, the preeclampsia may contribute to VEGFR-1/ PLGF and sVEGFR-1/membrane-bound.