Long-term follow-up of the cognitive function in children after intravitreal ranibizumab for retinopathy of prematurity.

PURPOSE: To evaluate the long-term cognitive function in children treated with intravitreal ranibizumab (IVR) for retinopathy of prematurity(ROP), and the impact of IVR on the growth and ocular development. METHODS: In this retrospective study, the premature children aged 4 to 9 years who received monotherapy of IVR (IVR group, n = 25) or monotherapy of laser photocoagulation (LP) (LP group, n = 33) for ROP, and the same age premature children with no ROP (Control group, n = 26) were enrolled from 2020 to 2022 in the pediatric fundus clinic of Shenzhen Eye Hospital. Main outcome measures were full-scale intelligence quotient (FSIQ) and index score using the Chinese version of the Wechsler intelligence scale for children-fourth edition (WISC-IV) and Wechsler preschool and primary scale of intelligence-fourth edition (WPPSI-IV). All children were examined and analyzed for growth and ocular development by recording the height, weight, head circumference, spherical equivalent (SE), best corrected visual acuity (BCVA) and axial length (AL). RESULTS: There were 17 children in IVR group, 17 in LP group, and 11 in Control group who received the WISC-IV assessment. There were no significant differences in FSIQ, verbal comprehension index, perceptual reasoning index, working memory index, processing speed index, general ability index and cognitive efficiency index among the three groups. There were 8 children in IVR group, 16 in LP group, and 15 in Control group who received the WPPSI-IV assessment. There were no significant differences in FSIQ, verbal comprehension index, visuospatial index, fluid reasoning index, working memory index, non-verbal index, general ability index and cognitive efficiency index among the three groups. There was no significant difference in BCVA among the three groups (P = 0.74), however, there is an increase for AL in IVR group when compared with LP group (22.60 ± 0.58 vs. 22.13 ± 0.84, P = 0.003), and the ROP patients of IVR group have a significant increase in the AL compared to the Control group(22.60 ± 0.58 vs. 22.03 ± 0.71, P < 0.0001). CONCLUSIONS: Children with a history of IVR have a similar cognitive function outcomes compared to those with a history of LP or were premature without ROP. ROP children with a history of IVR has longer AL than those treated with LP.

Refractive Status and Biometric Characteristics of Children With Familial Exudative Vitreoretinopathy.

Purpose: To compare biometric characteristics between patients with early-stage familial exudative vitreoretinopathy (FEVR) and healthy controls. Methods: This case-control study included 50 FEVR eyes in stage 1-2 and 50 control eyes matched by age, gender and spherical equivalent (SE). Biometric parameters including axial length (AL), white-to-white diameter (WTW), central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), pupil diameter, vitreous chamber depth, anterior and posterior corneal surface curvature radius (ACR and PCR), anterior lens surface curvature radius (ALR) and posterior lens surface curvature radius were measured using IOLMaster 700 and compared between cases and controls using paired t-test. Correlations between SE and biometric measures were assessed using Pearson correlation coefficient (r) in cases and controls. Results: Both FEVR cases and matched controls had a mean age of 7.6 years, 48% female and mean SE of -5.3 D (80% myopia). Compared to controls, FEVR eyes had smaller AL (P = 0.009), WTW (P = 0.001), ACD (P < 0.001), and ALR (P = 0.03), but larger CCT (P = 0.02) and LT (P = 0.01). In FEVR eyes, SE was negatively correlated with AL (r = -0.79, P < 0.001), positively correlated with ACR (r = 0.29, P = 0.04) and PCR (r = 0.33, P = 0.02), whereas in controls, SE was negatively correlated with AL (r = -0.82, P < 0.001) and LT (r = -0.34, P = 0.02), positively correlated with ALR (r = 0.29, P = 0.04). Conclusions: Patients at early stage of FEVR exhibited a unique eye morphology resembling ocular development arrest, which may help to develop screening and early detection tools for FEVR. In FEVR patients, myopia is very prevalent and significantly associated with corneal curvature increase.

LAC-GAN: Lesion attention conditional GAN for Ultra-widefield image synthesis.

Automatic detection of retinal diseases based on deep learning technology and Ultra-widefield (UWF) images plays an important role in clinical practices in recent years. However, due to small lesions and limited data samples, it is not easy to train a detection-accurate model with strong generalization ability. In this paper, we propose a lesion attention conditional generative adversarial network (LAC-GAN) to synthesize retinal images with realistic lesion details to improve the training of the disease detection model. Specifically, the generator takes the vessel mask and class label as the conditional inputs, and processes the random Gaussian noise by a series of residual block to generate the synthetic images. To focus on pathological information, we propose a lesion feature attention mechanism based on random forest (RF) method, which constructs its reverse activation network to activate the lesion features. For discriminator, a weight-sharing multi-discriminator is designed to improve the performance of model by affine transformations. Experimental results on multi-center UWF image datasets demonstrate that the proposed method can generate retinal images with reasonable details, which helps to enhance the performance of the disease detection model.

CXC chemokine ligand-10 promotes the accumulation of monocyte-like myeloid-derived suppressor cells by activating p38 MAPK signaling under tumor conditions.

CXC chemokine ligand-10 (CXCL10) is a small (10 kDa) secretory protein in the CXC subfamily of cytokines. CXCL10 has been reported to play an important role in antitumor immunity as a chemotactic factor. Tumor development is always accompanied by the formation of an immunosuppressive tumor microenvironment, and the role of CXCL10 in tumor immunosuppression remains unclear. Here, we reported that CXCL10 expression was significantly upregulated in mice with melanoma, and tumor cells secreted large amounts of CXCL10. Myeloid-derived suppressor cells (MDSCs) are an important part of the immunosuppressive tumor microenvironment. Our results showed that CXCL10 promoted the proliferation of monocyte-like (mo)-MDSCs by activating the p38 MAPK signaling pathway through CXCR3, which led to the abnormal accumulation of mo-MDSCs under tumor conditions. This finding provides a new understanding of the mechanism by which a tumor-induced immunosuppressive microenvironment forms and suggests that CXCL10 could be a potential intervention target for slowing tumor progression.

Refractive and biometrical characteristics of children with retinopathy of prematurity who received laser photocoagulation or intravitreal ranibizumab injection.

PURPOSE: To investigate the refractive and biometrical developments of children with retinopathy of prematurity (ROP) who received laser photocoagulation (LP) or intravitreal ranibizumab injection as treatment. METHODS: This case-control study involved cases with Zone II Stage 3 ROP. Fourteen children (28 eyes) who received single LP were included in the laser group, and 14 children (27 eyes) who received single intravitreal ranibizumab injection were included in the injection group. The mean age at operation was 37.00±1.72 and 36.36±1.66 weeks for the laser and injection groups, respectively (P=0.161), and refraction measurements and biometry were performed at the mean age of 5.00±1.63 and 5.00±0.94 years for the laser and injection groups, respectively (P=1.000). Spherical equivalent (SE) after mydriatic refraction and best corrected visual acuity (BCVA) were measured by refraction test. Central corneal thickness (CCT), anterior corneal surface curvature and curvature radius, anterior chamber depth (ACD), lens thickness (LT) and axial length (AL) were measured by biometry using the IOL Master700 biometric instrument (Carl Zeiss Meditec AG). The biometrical images were reanalysed using a self-developed program in MATLAB (R2016a, MathWorks, Inc.) to obtain additional eye parameters, including the curvatures of the posterior cornea and the anterior and posterior surfaces of the lens. SPSS (V.23.0) was used for statistical analysis. Independent sample t test was used to compare the eyeball biological and refractive state measures of the two groups, and Pearson correlation coefficient was used to evaluate the correlation between SE and the biological parameters. RESULTS: 1. (1) Cornea-related parameters: CCT (0.54±0.04mm vs 0.55±0.02mm, P>0.05), anterior corneal surface curvature radius (7.56±0.26 mm vs 7.67±0.43mm, P>0.05) and posterior corneal surface curvature radius (6.82±0.27mm vs 6.79±0.42mm, P>0.05). (2) ACD (3.21 ± 0.25mm vs 3.22 ± 0.19mm, P>0.05). (3) Lens-related parameters: anterior lens surface curvature radius (10.04±0.89mm vs 9.82±1.08mm, P>0.05), posterior lens surface curvature radius (5.49±0.55mm vs 5.92±0.73mm, P<0.05) and LT (3.80±0.14mm vs 3.59±0.16mm, P<0.05). (4) AL (21.82±1.07 vs 22.68±1.61, P<0.05). (5) Parameters related to refractive state: SE (-2.43±3.56 vs -0.53±3.12, P<0.05) and BCVA (log MAR, 0.17±0.14 vs 0.21±0.18, P>0.05). 2. (1) The SE of children in the laser group was positively correlated with LT (r=0.438, P<0.05), negatively correlated with ACD (r=-0.437, P<0.05) and had no significant correlation with other eyeball biological indicators (P>0.05). (2) The SE of children in the injection group was negatively correlated with AL (r=-0.537, P<0.05), positively correlated with CCT (r=0.455, P<0.05) and had no significant correlation with other eyeball biological indicators (P>0.05). CONCLUSION: LP and intravitreal ranibizumab injection as ROP treatments produce myopic refraction with increased degree of myopia in children who received LP than in children who received ranibizumab injection. The increased myopia after LP is due to the increases in LT and posterior lens curvature and a shallow ACD.

Cell-Penetrating Peptide TAT-HuR-HNS3 Suppresses Proinflammatory Gene Expression via Competitively Blocking Interaction of HuR with Its Partners.

Proinflammatory cytokines/chemokines are commonly regulated by RNA-binding proteins at posttranscriptional levels. Human Ag R (HuR)/embryonic lethal abnormal vision-like 1 (ELAVL1) is one of the well-characterized RNA-binding proteins that increases the stability of short-lived mRNAs, which encode proinflammatory mediators. HuR employs its nucleocytoplasmic shuttling sequence (HNS) domain, interacting with poly(ADP-ribose) polymerase 1 (PARP1), which accounts for the enhanced poly-ADP-ribosylation and cytoplasmic shuttling of HuR. Also by using its HNS domain, HuR undergoes dimerization/oligomerization, underlying the increased binding of HuR with proinflammatory cytokine/chemokine mRNAs and the disassociation of the miRNA-induced silencing complex from the targets. Therefore, competitively blocking the interactions of HuR with its partners may suppress proinflammatory mediator production. In this study, peptides derived from the sequence of the HuR-HNS domain were synthesized, and their effects on interfering HuR interacting with PARP1 and HuR itself were analyzed. Moreover, cell-penetrating TAT-HuR-HNS3 was delivered into human and mouse cells or administered into mouse lungs with or without exposure of TNF-α or LPS. mRNA levels of proinflammatory mediators as well as neutrophil infiltration were evaluated. We showed that TAT-HuR-HNS3 interrupts HuR-PARP1 interaction and therefore results in a lowered poly-ADP-ribosylation level and decreased cytoplasmic distribution of HuR. TAT-HuR-HNS3 also blocks HuR dimerization and promotes Argonaute 2-based miRNA-induced silencing complex binding to the targets. Moreover, TAT-HuR-HNS3 lowers mRNA stability of proinflammatory mediators in TNF-α-treated epithelial cells and macrophages, and it decreases TNF-α-induced inflammatory responses in lungs of experimental animals. Thus, TAT-HuR-HNS3 is a promising lead peptide for the development of inhibitors to treat inflammation-related diseases.

CXCL10 conditions alveolar macrophages within the premetastatic niche to promote metastasis.

Formation of the premetastatic niche is triggered by primary tumors and contributes to cancer metastasis. Evidence indicating the roles of macrophages in metastatic niche formation and organ-specific metastatic tropism has been steadily accumulating. However, the role of tissue-resident macrophages in the establishment of the premetastatic niche is not clearly defined. Here, we report that alveolar macrophages (AMs), which are lung tissue-resident macrophages, play a critical role in initiating the recruitment of monocytic myeloid-derived suppressor cells (mo-MDSCs) and the subsequent premetastatic niche formation by increasing CCL12 expression. We found that CXCL10 can induce CCL12 expression by activating CXCR3 and TLR4 in AMs. CXCR3/TLR4 deficiency or inhibition of its activity reduces CCL12 expression in AMs and subsequent mo-MDSC recruitment to the premetastatic niche, thereby attenuating lung metastasis. In addition, Ube2o is a negative modulator of CXCL10-induced CCL12 expression. Downregulation of Ube2o in AMs under tumor conditions enhances TAK1-NF-κB/ERK/JNK signaling and CXCL10-induced CCL12 expression by promoting TRAF6 polyubiquitination and inhibiting DDX3X degradation. Targeting mo-MDSC recruitment via the CXCL10-CXCR3/TLR4-CCL12 axis in AMs may have therapeutic potential for suppressing lung metastasis.

The downregulation of type I IFN signaling in G-MDSCs under tumor conditions promotes their development towards an immunosuppressive phenotype.

Tumors modify myeloid cell differentiation and induce an immunosuppressive microenvironment. Granulocytic myeloid-derived suppressor cells (G-MDSCs), the main subgroup of myeloid-derived suppressor cells (MDSCs), are immature myeloid cells (IMCs) with immunosuppressive activity and exist in tumor-bearing hosts. The reason why these cells diverge from a normal differentiation pathway and are shaped into immunosuppressive cells remains unclear. Here, we reported that the increase of granulocyte colony-stimulating factor (G-CSF) in mouse serum with tumor progression encouraged G-MDSCs to obtain immunosuppressive traits in peripheral blood through the PI3K-Akt/mTOR pathway. Importantly, we found that downregulation of type I interferon (IFN-I) signaling in G-MDSCs was a prerequisite for their immunosuppressive effects. Suppressor of cytokine signaling (SOCS1), the action of which is dependent on IFN-I signaling, inhibited the activation of the PI3K-Akt/mTOR pathway by directly interacting with Akt, indicating that the differentiation of immunosuppressive G-MDSCs involves a transition from immune activation to immune tolerance. Our study suggests that increasing IFN-I signaling in G-MDSCs may be a strategy for reprograming immunosuppressive myelopoiesis and slowing tumor progression.

The key players of parthanatos: opportunities for targeting multiple levels in the therapy of parthanatos-based pathogenesis.

Parthanatos is a form of regulated cell death involved in the pathogenesis of many diseases, particularly neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Parthanatos is a multistep cell death pathway cascade that involves poly (ADP-ribose) polymerase 1 (PARP-1) overactivation, PAR accumulation, PAR binding to apoptosis-inducing factor (AIF), AIF release from the mitochondria, nuclear translocation of the AIF/macrophage migration inhibitory factor (MIF) complex, and MIF-mediated large-scale DNA fragmentation. All the key players in the parthanatos pathway are pleiotropic proteins with diverse functions. An in-depth understanding of the structure-based activity of the key factors, and the biochemical mechanisms of parthanatos, is crucial for the development of drugs and therapeutic strategies. In this review, we delve into the key players of the parthanatos pathway and reveal the multiple levels of therapeutic opportunities for treating parthanatos-based pathogenesis.

Propionate and Butyrate Produced by Gut Microbiota after Probiotic Supplementation Attenuate Lung Metastasis of Melanoma Cells in Mice.

SCOPE: The beneficial effects of probiotics in reducing gastrointestinal inflammation and in preventing colorectal cancer have been reported, but the mechanism underlying the immunomodulatory effect of probiotics in inhibiting extra-intestinal tumor progression remains unclear. METHODS AND RESULTS: This study shows that probiotic supplementation attenuate lung metastasis of melanoma cells in mice. Feeding mice with VSL#3 probiotics change the composition and proportion of gut microbiota. The changes in gut bacteria composition, such as in the abundance of Lachnospiraceae, Streptococcus, and Lachnoclostridium, are associated with the production of short-chain fatty acids in the gut. The concentrations of propionate and butyrate are upregulated in gut and blood after feeding VSL#3, and the increase in propionate and butyrate levels promotes the expression of chemokine (C-C motif) ligand 20 (CCL20) in lung endothelial cells and the recruitment of T helper 17 (Th17) cells to the lungs via the CCL20/chemokine receptor 6 axis. The recruitment of Th17 cells decreases the number of tumor foci in lungs and attenuates the lung metastasis of melanoma cells in mice. CONCLUSIONS: The results provide new information on the role and mechanisms of action of probiotics in attenuating extra-intestinal tumor metastasis.

Cross-attention multi-branch network for fundus diseases classification using SLO images.

Fundus diseases classification is vital for the health of human beings. However, most of existing methods detect diseases by means of single angle fundus images, which lead to the lack of pathological information. To address this limitation, this paper proposes a novel deep learning method to complete different fundus diseases classification tasks using ultra-wide field scanning laser ophthalmoscopy (SLO) images, which have an ultra-wide field view of 180-200˚. The proposed deep model consists of multi-branch network, atrous spatial pyramid pooling module (ASPP), cross-attention and depth-wise attention module. Specifically, the multi-branch network employs the ResNet-34 model as the backbone to extract feature information, where the ResNet-34 model with two-branch is followed by the ASPP module to extract multi-scale spatial contextual features by setting different dilated rates. The depth-wise attention module can provide the global attention map from the multi-branch network, which enables the network to focus on the salient targets of interest. The cross-attention module adopts the cross-fusion mode to fuse the channel and spatial attention maps from the ResNet-34 model with two-branch, which can enhance the representation ability of the disease-specific features. The extensive experiments on our collected SLO images and two publicly available datasets demonstrate that the proposed method can outperform the state-of-the-art methods and achieve quite promising classification performance of the fundus diseases.

Distinct Ring1b complexes defined by DEAD-box helicases and EMT transcription factors synergistically enhance E-cadherin silencing in breast cancer.

Ring1b is a core subunit of polycomb repressive complex 1 (PRC1) and is essential in several high-risk cancers. However, the epigenetic mechanism of Ring1b underlying breast cancer malignancy is poorly understood. In this study, we showed increased expression of Ring1b promoted metastasis by weakening cell-cell adhesions of breast cancer cells. We confirmed that Ring1b could downregulate E-cadherin and contributed to an epigenetic rewiring via PRC1-dependent function by forming distinct complexes with DEAD-box RNA helicases (DDXs) or epithelial-mesenchymal transition transcription factors (EMT TFs) on site-specific loci of E-cadherin promoter. DDXs-Ring1b complexes moderately inhibited E-cadherin, which resulted in an early hybrid EMT state of epithelial cells, and EMT TFs-Ring1b complexes cooperated with DDXs-Ring1b complexes to further repress E-cadherin in mesenchymal-like cancer cells. Clinically, high expression of Ring1b with DDXs or EMT TFs predicted low levels of E-cadherin, metastatic behavior, and poor prognosis. These findings provide an epigenetic regulation mechanism of Ring1b complexes in E-cadherin expression. Ring1b complexes may be potential therapeutic targets and biomarkers for diagnosis and prognosis in invasion breast cancer.

Study of the Biological Developmental Characteristics of the Eye in Children After Laser Surgery for the Treatment of Retinopathy of Prematurity.

OBJECTIVE: To observe the differences in ocular biology between premature infants who had undergone retinal laser photocoagulation (LP) for retinopathy of prematurity (ROP) and full-term infants and to investigate the relationships between these differences and the development of the refractive state. METHODS: This retrospective, cross-sectional study included 25 children (50 eyes) who had undergone laser treatment for aggressive posterior retinopathy of prematurity (AP-ROP), ROP in zone I requiring treatment, or ROP in zone II requiring treatment in the posterior pole (laser group) and 29 full-term infants (58 eyes) who had not (control group). Basic information, spherical equivalent (SE), and best corrected visual acuity (BCVA) were collected from the two groups. Their mean ages were 7.32 ± 2.85 and 7.34 ± 2.57 years, respectively (t = -0.047, P = 0.96). Ocular biology data were measured using an IOL Master 700 instrument (Carl Zeiss Meditec AG) and the data were processed using MATLAB (R2016a, Mathworks Inc.). The data markers included central corneal thickness (CCT), anterior and posterior surface corneal curvature radius (CCR), anterior chamber depth (ACD), lens thickness (LT), lens anterior surface curvature radius, lens posterior surface curvature radius, and eye axis length (AL). Optometric data were collected simultaneously and all BCVA values were converted to the logarithm of the minimum angle of resolution (LogMAR) for analysis. The data were statistically analyzed using SPSS software (V.23.0). Independent sample t-tests were used for the assessment of ocular biology and refractive indices in both groups of children and Pearson correlation coefficients were used to evaluate the correlations between age, gestational age at birth and ocular biology structural parameters. P < 0.05 was considered statistically significant. RESULTS: Comparisons of ocular biomarkers, refractive status, and BCVA between children in the laser and control groups showed relationships among ocular biomarkers, including the corneal-related parameters of CCT (0.54 ± 0.04 mm and 0.56 ± 0.03 mm, t = -2.116, P < 0.05), anterior surface CCR (7.53 ± 0.33 mm and 7.84 ± 0.30 mm, t = -5.063, P < 0.05), posterior surface CCR (6.75 ± 0.34 mm and 7.03 ± 0.24 mm, t = -4.864, P < 0.05); as well as those related to anterior chamber depth (ACD) were 3.24 ± 0.26 mm and 3.64 ± 0.26 mm, respectively (t = -8.065, P < 0.05), lens-related parameters (LT) were 3.80 ± 0.19 mm and 3.45 ± 0.16 mm, respectively (t = 10.514, P < 0.05); anterior lens surface curvature radius were 10.02 ± 0.93 mm and 10.52 ± 0.85 mm, respectively (t = -2.962, P < 0.05); posterior lens surface curvature radius were 5.55 ± 0.51 mm and 5.80 ± 0.36 mm, respectively (t = -2.917, P < 0.05), and ocular axis (AL) were 22.60 ± 1.42 mm and 23.45 ± 1.23 mm, respectively (t = -3.332, P < 0.05). Moreover, comparison of refractive status and BCVA between two groups of children showed an SE of -1.23 ± 3.38 D and -0.07 ± 2.00 D (t = -2.206, P < 0.05) and LogMAR (BCVA) of 0.12 ± 0.13 and 0.05 ± 0.11 (t = 3.070, P < 0.05). Analysis of the correlations between age and ocular biomarkers and refractive status of children in the laser and control groups showed correlations between age and ocular biomarkers in the two groups, in which age in the laser group was positively correlated with AL (r = 0.625, P < 0.05) but not with other biomarkers (P > 0.05). Age in the control group was negatively correlated with CCT, ACD, and AL (r = 0.303, 0.468, 0.703, P < 0.05), as well as with LT (r = -0.555, P < 0.05), with no correlation with other biomarkers (P > 0.05). Analysis of the correlation between age and refractive status of children in both groups showed that the age of children in both laser and control groups was negatively correlated with SE (r = -0.528, -0.655, P < 0.05) and LogMAR (BCVA) (r = -0.538, -0.542, P < 0.05). Analysis of the correlations between refractive status and ocular biomarkers in children in the laser and control groups showed that the refractive status in children in the laser group was negatively correlated with AL (r = -0.773, P < 0.05) but not with other biomarkers in this group (P > 0.05). The refractive status of children in the control group was negatively correlated with ACD and AL (r = -0.469, -0.734, P < 0.05), positively correlated with LT (r = 0.364, P < 0.05), and was not correlated with other biomarkers in this group (P > 0.05). Analysis of the correlations of gestational age at birth with ocular biomarkers and refractive status in children in the laser group showed a positive correlation between gestational age at birth and AL (r = 0.435, P < 0.05) but no other correlations with the other biomarkers (P > 0.05). Moreover, gestational age at birth was negatively correlated with SE (r = -0.334, P < 0.05) and LogMAR (BCVA) (r = -0.307, P < 0.05) in children in the laser group. CONCLUSIONS: Compared to full-term infants, the development of CCT, ACD, LT, and AL was relatively delayed after ROP laser surgery, resulting in thin central corneal thickness, steep corneas, shallow anterior chambers, thicker lenses, "rounder" lens morphology, increased refractive power, and short eye axes, leading to the development of myopia. The changes in refractive status were mainly influenced by increased lens thickness. The results of this study showed that the lower the gestational age at birth, the greater the effects on emmetropization in children after ROP, and the more likely the development of myopia.

Poly(ADP-ribosyl)ation enhances HuR oligomerization and contributes to pro-inflammatory gene mRNA stabilization.

Poly(ADP-ribosyl)ation (PARylation) is an important post-translational modification mainly catalyzed by poly-ADP-ribose polymerase 1 (PARP1). In addition to having important roles in DNA damage detection and repair, it functions in gene expression regulation, especially at the posttranscriptional level. Embryonic lethal abnormal vision-like 1/human antigen R (ELAVL/HuR), a canonical 3' untranslated region AU-rich element-binding protein, is a crucial mRNA-stabilizing protein that protects target mRNAs from RNA-destabilizing protein- or microRNA-induced silencing complex (miRISC)-mediated degradation. Additionally, in some cases, HuR itself either promotes or suppresses translation. Here, we demonstrated that in response to inflammatory stimuli, the PARylation of HuR, mostly at the conserved D226 site, by PARP1 increased the formation of the HuR oligomer/multimer, and HuR oligomerization promoted the disassociation of miRISC and stabilized the pro-inflammatory gene mRNAs. The prevention of PARP1 activation or HuR oligomerization attenuated lipopolysaccharide-induced inflammatory gene expression and the airway recruitment of neutrophils in mouse lungs. The present study verified a novel mechanism of PARP1 and HuR PARylation in the RNA stability regulation, increasing our understanding of how PARP1 regulates gene expression.

AMD-GAN: Attention encoder and multi-branch structure based generative adversarial networks for fundus disease detection from scanning laser ophthalmoscopy images.

The scanning laser ophthalmoscopy (SLO) has become an important tool for the determination of peripheral retinal pathology, in recent years. However, the collected SLO images are easily interfered by the eyelash and frame of the devices, which heavily affect the key feature extraction of the images. To address this, we propose a generative adversarial network called AMD-GAN based on the attention encoder (AE) and multi-branch (MB) structure for fundus disease detection from SLO images. Specifically, the designed generator consists of two parts: the AE and generation flow network, where the real SLO images are encoded by the AE module to extract features and the generation flow network to handle the random Gaussian noise by a series of residual block with up-sampling (RU) operations to generate fake images with the same size as the real ones, where the AE is also used to mine features for generator. For discriminator, a ResNet network using MB is devised by copying the stage 3 and stage 4 structures of the ResNet-34 model to extract deep features. Furthermore, the depth-wise asymmetric dilated convolution is leveraged to extract local high-level contextual features and accelerate the training process. Besides, the last layer of discriminator is modified to build the classifier to detect the diseased and normal SLO images. In addition, the prior knowledge of experts is utilized to improve the detection results. Experimental results on the two local SLO datasets demonstrate that our proposed method is promising in detecting the diseased and normal SLO images with the experts labeling.

MicroRNA 449c Mediates the Generation of Monocytic Myeloid-Derived Suppressor Cells by Targeting STAT6.

Myeloid-derived suppressor cells (MDSCs) promote tumour progression by contributing to angiogenesis, immunosuppression, and immunotherapy resistance. Although recent studies have shown that microRNAs (miRNAs) can promote the expansion of MDSCs in the tumour environment, the mechanisms involved in this process are largely unknown. Here, we report that microRNA 449c (miR-449c) expression was upregulated in myeloid progenitor cells upon activation of C-X-C motif chemokine receptor 2 (CXCR2) under tumour conditions. MiR-449c upregulation increased the generation of monocytic MDSCs (mo-MDSCs). The increased expression of miR-449c could target STAT6 mRNA in myeloid progenitor cells to shift the differentiation balance of myeloid progenitor cells and lead to an enhancement of the mo-MDSCs population in the tumour environment. Thus, our results demonstrate that the miR-449c/STAT6 axis is involved in the expansion of mo-MDSCs from myeloid progenitor cells upon activation of CXCR2, and thus, inhibition of miR-449c/STAT6 signalling may help to attenuate tumour progression.

c­Abl­mediated tyrosine phosphorylation of DNA damage response proteins and implications in important cellular functions (Review).

Tyrosine phosphorylation is an essential post­translational protein modification catalyzed by tyrosine kinases. c­Abl is a crucial non­receptor tyrosine kinase, which is most commonly activated by auto­phosphorylation, DNA damage and by interacting with other protein kinases. DNA damage response (DDR) proteins stimulated by DNA lesions or chromatin alterations recruit the DNA repair and cell cycle checkpoint machinery to restore genome integrity and cellular homeostasis. The fundamental roles of activated c­Abl tyrosine kinase in cellular response pathways have been intensively and extensively investigated and in recent years, a number of c­Abl protein binding partners have been determined; however, the functional roles of these molecules remain to be determined. The present review aimed to summarize the DDR proteins phosphorylated by c­Abl tyrosine kinase that have been identified to date, in addition to the functional outcomes of these phosphotyrosine events. Notably, it has been discovered that c­Abl tyrosine kinase can bind with and phosphorylate DDR proteins at different tyrosine sites, which serve distinct roles in various cellular contexts.

Enzymatically inactive OGG1 binds to DNA and steers base excision repair toward gene transcription.

8-Oxoguanine DNA glycosylase1 (OGG1)-initiated base excision repair (BER) is the primary pathway to remove the pre-mutagenic 8-oxo-7,8-dihydroguanine (8-oxoG) from DNA. Recent studies documented 8-oxoG serves as an epigenetic-like mark and OGG1 modulates gene expression in oxidatively stressed cells. For this new role of OGG1, two distinct mechanisms have been proposed: one is coupled to base excision, while the other only requires substrate binding of OGG1--both resulting in conformational adjustment in the adjacent DNA sequences providing access for transcription factors to their cis-elements. The present study aimed to examine if BER activity of OGG1 is required for pro-inflammatory gene expression. To this end, Ogg1/OGG1 knockout/depleted cells were transfected with constructs expressing wild-type (wt) and repair-deficient mutants of OGG1. OGG1's promoter enrichment, oxidative state, and gene expression were examined. Results showed that TNFα exposure increased levels of oxidatively modified cysteine(s) of wt OGG1 without impairing its association with promoter and facilitated gene expression. The excision deficient K249Q mutant was even a more potent activator of gene expression; whereas, mutant OGG1 with impaired substrate recognition/binding was not. These data suggested the interaction of OGG1 with its substrate at regulatory regions followed by conformational adjustment in the adjacent DNA is the primary mode to modulate inflammatory gene expression.

RNF8 promotes efficient DSB repair by inhibiting the pro-apoptotic activity of p53 through regulating the function of Tip60.

OBJECTIVES: RING finger protein 8 (RNF8) is an E3 ligase that plays an essential role in DSB repair. p53 is a well-established tumour suppressor and cellular gatekeeper of genome stability. This study aimed at investigating the functional correlations between RNF8 and p53 in DSB damage repair. MATERIALS AND METHODS: In this article, wild-type, knockout and shRNA-depleted HCT116 and U2OS cells were stressed, and the roles of RNF8 and p53 were examined. RT-PCR and Western blot were utilized to investigate the expression of related genes in damaged cells. Cell proliferation, apoptosis and neutral cell comet assays were applied to determine the effects of DSB damage on differently treated cells. DR-GFP, EJ5-GFP and LacI-LacO targeting systems, flow cytometry, mass spectrometry, IP, IF, GST pull-down assay were used to explore the molecular mechanism of RNF8 and p53 in DSB damage repair. RESULTS: We found that RNF8 knockdown increased cellular sensitivity to DSB damage and decreased cell proliferation, which was correlated with high expression of the p53 gene. RNF8 improved the efficiency of DSB repair by inhibiting the pro-apoptotic function of p53. We also found that RNF8 restrains cell apoptosis by inhibiting over-activation of ATM and subsequently reducing p53 acetylation at K120 through regulating Tip60. CONCLUSIONS: Taken together, these findings suggested that RNF8 promotes efficient DSB repair by inhibiting the pro-apoptotic activity of p53 through regulating the function of Tip60.

Lung resided monocytic myeloid-derived suppressor cells contribute to premetastatic niche formation by enhancing MMP-9 expression.

In cancer patients, the prevalence of myeloid-derived suppressor cells (MDSCs) is correlated with the degree of malignancy. In the present study, we investigated the role of circulating M-MDSCs in premetastatic niche formation using a mouse syngeneic tumor model and found that there was an increased frequency of M-MDSCs in the peripheral blood of tumor-bearing mice. M-MDSCs tracking and lung tissue histological analyses revealed that the malignant conditions promote the residence of circulating M-MDSCs and increased tumor cell arrest in the lungs. We further found that MMP-9 expression was increased in the circulating M-MDSCs and the administration of an MMP-9 inhibitor suppressed M-MDSCs transplantation-induced tumor cell arrest in the lung. Therefore, our findings suggest that the expansion of circulating M-MDSCs during tumor progression contributes to premetastatic niche formation by increasing MMP-9 expression.