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In this study, we used a combination of chemical and biological pretreatment methods to extract cellulose from corn straw with a relative content of 92.40%. The adsorption performance and mechanism of the prepared porous carbon were investigated using synthetic dye malachite green (MG) and antibiotic tetracycline hydrochloride (TC) as adsorption models. The kinetic studies suggested that the adsorption followed the pseudo-second-order model and Bangham model. The Freundlich isotherm model fitted the adsorption data best for both MG and TC. The thermodynamic studies showed that the adsorption of MG and TC by adsorbents were spontaneous and endothermic in nature. In addition, the adsorption performance was maintained at 50% of the original value after five cycles. More importantly, this method not only improved the adsorption performance of prepared porous carbon materials but also provides a reference for the application of other lignocellulosic materials for cellulose extraction.

Previouswork in slogan generation focused on utilising slogan skeletons mined from existing slogans. While some generated slogans can be catchy, they are often not coherent with the company’s focus or style across their marketing communications because the skeletons are mined from other companies’ slogans. We propose a sequence-to-sequence (seq2seq) Transformer model to generate slogans from a brief company description. A naïve seq2seq model fine-tuned for slogan generation is prone to introducing false information. We use company name delexicalisation and entity masking to alleviate this problem and improve the generated slogans’ quality and truthfulness. Furthermore, we apply conditional training based on the first words’ part-of-speech tag to generate syntactically diverse slogans. Our best model achieved a ROUGE-1/-2/-L $\mathrm{F}_1$ score of 35.58/18.47/33.32. Besides, automatic and human evaluations indicate that our method generates significantly more factual, diverse and catchy slogans than strong long short-term memory and Transformer seq2seq baselines.

In real-world applications, text classification models often suffer from a lack of accurately labelled documents. The available labelled documents may also be out of domain, making the trained model not able to perform well in the target domain. In this work, we mitigate the data problem of text classification using a two-stage approach. First, we mine representative keywords from a noisy out-of-domain data set using statistical methods. We then apply a dataless classification method to learn from the automatically selected keywords and unlabelled in-domain data. The proposed approach outperformed various supervised learning and dataless classification baselines by a large margin. We evaluated different keyword selection methods intrinsically and extrinsically by measuring their impact on the dataless classification accuracy. Last but not least, we conducted an in-depth analysis of the behaviour of the classifier and explained why the proposed dataless classification method outperformed supervised learning counterparts.

Avanafil is a phosphodiesterase type 5 inhibitor which is used to treat erectile dysfunction in men. The process-related impurities of avanafil were investigated, and four kinds of impurities in several laboratory batches with a content of 0.29-1.63% were detected by the newly developed gradient ultra-high performance liquid chromatography (UPLC). Based on the synthesis route and UPLC-MS research, the impurities are inferred as Imp-A, Imp-B, Imp-C and Imp-D. The structures of the impurities were inferred from LC-MS studies and confirmed by synthesis, followed by spectroscopic characterization such as NMR and mass spectrometry. Especially, the synthesis of Imp-D is firstly reported. The drug-related substances can be separated well by efficient and selective ultra-high performance liquid chromatography on a Waters ACQUITY HSS C18 (50 × 2.1 mm, particle size 1.8 μm) column at 35 °C, with the mobile phase consisting of ammonium formate (20 mM) and acetonitrile, and the detection at 239 nm with a DAD detector. The method was validated in terms of specificity, linearity, precision, accuracy and sensitivity, and satisfactory results were obtained. The results indicated this developed UPLC method for avanafil and the proposed synthesis mechanism can be used for quality control purposes as required by regulatory agencies to ensure the safety and efficacy of the product.

Objective. DNA methylation played a vital role in the progression of diabetic retinopathy. In this study, we aimed to explore the role of DNA cytosine-5-methyltransferase 1 (DNMT1) in the development of early diabetic retinopathy and its potential underlying mechanism. Methods. Eight-week-old healthy Mongolian gerbils were used to establish type 1 diabetes using streptozotocin (STZ). Alteration of weight, fasting blood glucose, density of RGCs (Tuj1-labeled), and H&E-stained retinal cross sections were applied to evaluate the diabetic retinopathy mouse model. The global DNA methylation level of the retina at different time points after STZ injection was measured using the global methylation assay. Western blot was used to detect the protein expression of DNMT1, DNA methyltransferase 3A (DNMT3A), and 3B (DNMT3B). Quantitative reverse transcription-polymerase chain reactions (qRT-PCR) and western blot were used to determine the expression of CDKN2B. Cell proliferation and cell cycle were evaluated by the MTS assay and flow cytometry. Results. STZ injection caused the increased global DNA methylation level, which reached a maximum at 6 weeks after injection. Moreover, STZ injection caused the damage of RGCs. At 6 weeks after STZ injection, the expression levels of DNMT1 and DNMT3B were significantly increased in the STZ group. DNMT1-induced DNA hypermethylation inhibited the expression of CDKN2B (a negative regulator of cell cycle). DNMT1-mediated DNA methylation facilitated RGC proliferation via regulating the expression of CDKN2B. Conclusion. DNMT1-mediated DNA methylation played an important role in STZ-induced diabetic retinopathy via modulating CDKN2B expression.

Contextual advertising provides advertisers with the opportunity to target the context which is most relevant to their ads. However, its power cannot be fully utilized unless we can target the page content using fine-grained categories, e.g., "coupe" vs. "hatchback" instead of "automotive" vs. "sport". The widely used advertising content taxonomy (IAB taxonomy) consists of 23 coarse-grained categories and 355 fine-grained categories. With the large number of categories, it becomes very challenging either to collect training documents to build a supervised classification model, or to compose expert-written rules in a rule-based classification system. Besides, in fine-grained classification, different categories often overlap or co-occur, making it harder to classify accurately. In this work, we propose wiki2cat, a method to tackle the problem of large-scaled fine-grained text classification by tapping on Wikipedia category graph. The categories in IAB taxonomy are first mapped to category nodes in the graph. Then the label is propagated across the graph to obtain a list of labeled Wikipedia documents to induce text classifiers. The method is ideal for large-scale classification problems since it does not require any manually-labeled document or hand-curated rules or keywords. The proposed method is benchmarked with various learning-based and keyword-based baselines and yields competitive performance on both publicly available datasets and a new dataset containing more than 300 fine-grained categories., Accepted to TextGraphs-15 Workshop @ NAACL 2021

Background Glaucoma is hallmarked with the death of retinal neurons in the ganglion cell layer, which results in irreversible vision loss. The abnormal levels of miRNA have been associated with glaucoma. Our study purposed to explore the underlying molecule mechanism of miR-93-5p in NMDA-induced glaucoma. Methods The Sprague-Dawley (SD) rats were used for the establishment of glaucoma model with the injection of NMDA. Vision behavior test were performed on the glaucoma rats. MiR-93-5p expression was determined by real-time PCR. The levels of autophagy-related protein and PTEN were assessed by Western blot assays. TUNEL assay and flow cytometry were performed to analyze cell apoptosis in vivo and in vitro, respectively. And cell viability was examined by CKK-8 assay. The relationship between miR-93-5p and PTEN was confirmed by Dual-Luciferase reporter gene system. Results NMDA-induced glaucoma rats exhibited less time in the dark box, suggesting the recession of their vision. Moreover, the retinal ganglion cell (RGC) viability was reduced not only in the glaucoma rat models but also in the glaucoma RGC models. The autophagy-related protein was obviously increased in the NMDA-treated rats or RGCs. PTEN regulated the autophagy of RGCs through AKT/mTOR pathway in NMDA-treated RGCs. MiR-93-5p could target regulate PTEN negatively, and exhibit the similar effect of 3-MA on the survival of RGCs. Conclusion Up-regulation of miR-93-5p binding with PTEN suppressed the autophagy of RGCs through AKT/mTOR pathway in NMDA-induced glaucoma.

Fomes fomentarius (L.) J. J. Kickx (FF), a fungal hyphae causing tree decay, has confused people for many years on how to deal with it economically and efficiently. In this study, fungal hyphae from FF was first time used as the carbon source to prepare biomass carbon material (BCFF) material via a simple method including carbonization at 600 °C and sodium hydroxide activation. Notably, BCFF-Na4-700-60 (with alkali-carbon ratio of 4:1 and heated at 700 °C for 60 min) showed a large specific surface area (3352 m2 g−1) and a high pore volume (2.29 cm3 g−1). Moreover, the synthetic dye brilliant green (BG) was selected as the dye model to investigate the adsorption performance and mechanism. The maximum adsorption capacity of BCFF-Na4-700-60 was 3166 mg g−1at pH value of 9, which is superior to those of the great majority of adsorbents. After ten cycles, the adsorption capacity could still be maintained at about 53% of the original value. The results of these studies indicate that biomass carbon materials modified with forest pathogen have excellent adsorption capacity and cycling stability, which could be considered as a potential adsorbent for treatment of wastewater from dyeing industry. More importantly, this rapid and effective method can be further applied to other similar fungal hyphae.

We consider a document classification problem where document labels are absent but only relevant keywords of a target class and unlabeled documents are given. Although heuristic methods based on pseudo-labeling have been considered, theoretical understanding of this problem has still been limited. Moreover, previous methods cannot easily incorporate well-developed techniques in supervised text classification. In this paper, we propose a theoretically guaranteed learning framework that is simple to implement and has flexible choices of models, e.g., linear models or neural networks. We demonstrate how to optimize the area under the receiver operating characteristic curve (AUC) effectively and also discuss how to adjust it to optimize other well-known evaluation metrics such as the accuracy and F1-measure. Finally, we show the effectiveness of our framework using benchmark datasets., EMNLP-IJCNLP2019, fix typos in Theorem 1: change $\pi$ and $\pi'$ to $\theta$ and $\theta'$

Physalis alkekengi L. husk (PH) is a waste product discarded during agricultural production. Improper disposal of large amounts of PH can lead to environmental pollution of water and air. In this work, a porous carbon material was prepared for the first time from PH and denoted as PCPH. The structures and surface properties of PCPH were characterized using TGA, SEM, XRD, FT-IR, N 2 adsorption/desorption, Raman spectroscopy, and XPS. The specific surface area of PCPH was as high as 3502 m2/g, and the total pore volume was 2.24 cm3/g. Malachite green (MG) was used as a model dye for evaluating the adsorption performance of PCPH. When the pH was 9, the maximum adsorption capacity of PCPH reached 1989 mg/g. Fast adsorption of MG reached 1016 mg/g in the first 5 min. The adsorption data of PCPH was fitted with kinetics and isotherm models, and the thermodynamics were analyzed. The adsorption mechanism of MG was also analyzed. The removal rate of MG still reached 89% after 10 cycles. In summary, PCPH has excellent application potential in environmental water pollution treatment.

Supplemental Digital Content is available in the text., Rationale: The effectiveness of transplanted bone marrow mesenchymal stem cells (MSCs) for cardiac repair has been limited; thus, strategies for optimizing stem-cell–based myocardial therapy are needed. Objective: The present study was designed to test our central hypothesis that hypoxia-preconditioned MSCs (HP-MSCs) are more effective than MSCs cultured under ambient oxygen levels for the treatment of myocardial injury in a large-scale (N=49), long-term (9 months), nonhuman primate (Cynomolgous monkeys) investigation. Methods and Results: MSCs were engineered to express green fluorescent protein, cultured under ambient oxygen or 0.5% oxygen (HP-MSCs) for 24 hours and then tested in the infarcted hearts of Cynomolgus monkeys (1×107 cells per heart). Hypoxia preconditioning increased the expression of several prosurvival/proangiogenic factors in cultured MSCs, and measurements of infarct size and left-ventricular function at day 90 after myocardial infarction were significantly more improved in monkeys treated with HP-MSCs than in monkeys treated with the control vehicle; functional improvements in normal cultured bone marrow mesenchymal stem cells–treated monkeys were not significant. HP-MSCs transplantation was also associated with increases in cardiomyocyte proliferation, vascular density, myocardial glucose uptake, and engraftment of the transplanted cells and with declines in endogenous cell apoptosis, but did not increase the occurrence of arrhythmogenic complications. Conclusions: Hypoxia preconditioning improved the effectiveness of MSCs transplantation for the treatment of myocardial infarction in nonhuman primates without increasing the occurrence of arrhythmogenic complications, which suggests that future clinical trials of HP-MSCs transplantation are warranted.

Background The effect of liver resection on acetaminophen metabolism and whether it is affected by residual liver volume is poorly understood. Methods We investigated the effects of liver resection on acetaminophen metabolism in a single centre, prospective observational, case–control study of inpatients. Patients undergoing liver resection were administered therapeutic post-operative acetaminophen. Glutathione and urinary acetaminophen metabolites were measured over the first three post-operative days and compared between patients with low (Group A) and high (Group B) residual liver volume. Results 41 patients (41% female, median age 62 [IQR 53–72] years) were included. Mean urinary cysteine levels increased significantly from post-operative day 1 to 2 (578.0 mg/day 95% CI 478.9–677.1 vs. 775.4 mg/day, 95% CI 625.7–925.1; p = 0.03). Group A ( n = 11) had significantly higher median levels of cysteine (day 1, 464.3 mg/day [IQR 355.6–582.0]; day 3, 717.6 mg/day [IQR 423.5–1104.0]) compared to Group B ( n = 11): day 1, 545.4 mg/day (IQR 346.9–843.5); day 3, 508.1 mg/day (IQR 390.8–788.4; p = 0.048). No significant difference was observed in glutathione or 5-oxoproline levels between the groups. Conclusion Low residual liver volume results in altered acetaminophen metabolism, however, no evidence of glutathione deficiency was observed. Therapeutic acetaminophen is safe after major liver resection provided liver function is adequate.

Nowadays, people have a boat of themselves become more and more popular. People use their boat for fishing trip and taking holiday. However, most of them do not want to take care of their boat by themselves. One of the reasons might be the place of a boat occupied. Recently, a method has been used is to store boat on the Boat Hotel. They pay for the rent of a boat garage and also hire someone to take care of their boat. Place the boat on the boat shelf with several layers is the most common method. They use forklift to take in/out the boat when boat owner need use their boat. On the conditional of this situation, if we want to take a boat which is inside of boat shelf, then we need take all outside boat out. It’s really an inefficiency way, so we need improve it. In this study, we aim to design a Boat Storage System based on the existing shelf and meet all requirement of existing boat. This system should be reliable, efficient, economic, operable and flexible. The main function of the Boat Storage System is to take in/off the boat more quickly and automatically and efficiently. The system is similar with the stereo parking garage. Which have a paternoster controlled by PLC program. Consider of the boat is heavier than the car. Our storage structure should be more stable. Our design only need one person to operate it. The whole process will cost few seconds. This building will be established in the water. Therefore, the owner only need to push the button and then the boat will be prepared in the water automatically. The modelling and assembly was designed in Autodesk Inventor 2017. This hardware circuit of PLC was drawn in AutoCAD. The software to design the PLC is GX Works 2. And we used ANSYS Workbench 17.2 to analysis the structure. The analysis will prove the structure is safety and strong enough. And the simulation will prove the system is possible. Our conclusion is that this system has a good future and general application in the market.

Programmed death ligand-1 (PD-L1) plays a critical role in T-cell regulatory function. Here, we report a newly discovered effect of PD-L1 on angiogenesis. We demonstrate that PD-L1 and its receptor CD80, but not PD-1, are expressed by primary murine lung and heart vascular endothelial cells and the miscrovascular endothelial cell line (MS1) at both the mRNA and protein levels in vitro. The inhibition of PD-L1 or CD80 expression in MS1 cells, by small-interfering RNA transfection, led to a significant up-regulation of vascular endothelial growth factor receptor 2 expression and cell proliferation levels in MS1 cells. Furthermore, MS1 cells were found to have a significantly lower proliferation and vascular endothelial growth factor receptor 2 expression levels when they were co-cultured with PD-L1-expressing normal corneal epithelial cells, as compared to MS1 cells co-cultured with PD-L1(-/-) corneal epithelial cells. In a suture-induced corneal angiogenesis model, we observed a significantly higher level of angiogenic response in PD-L1(-/-) knockout mice as compared to wild-type mice, although there was no significant difference in the expression of inflammatory cytokines (interleukin-1α, interleukin-1β, or tumor necrosis factor-α) or the infiltration of innate immune cells (neutrophils and macrophages) between the two groups. We conclude that the expression of PD-L1 in both vascular endothelial cells and corneal epithelial cells regulates corneal angiogenesis.

Programmed death-ligand (PD-L)1 and PD-L2, newer B7 superfamily members, are implicated in the negative regulation of immune responses and peripheral tolerance. To examine their function in alloimmunity, we used the murine model of orthotopic corneal transplantation. We demonstrate that PD-L1, but not PD-L2, is constitutively expressed at high levels by the corneal epithelial cells, and at low levels by corneal CD45+ cells in the stroma, whereas it is undetectable on stromal fibroblasts and corneal endothelial cells. Inflammation induces PD-L1 up-regulation by corneal epithelial cells, and infiltration of significant numbers of PD-L1+CD45+CD11b+ cells. Blockade with anti-PD-L1 mAb dramatically enhances rejection of C57BL/6 corneal allografts by BALB/c recipients. To examine the selective contribution of donor vs host PD-L1 in modulating allorejection, we used PD-L1−/− mice as hosts or donors of combined MHC and minor H-mismatched corneal grafts. BALB/c grafts placed in PD-L1−/− C57BL/6 hosts resulted in pronounced T cell priming in the draining lymph nodes, and universally underwent rapid rejection. Allografts from PD-L1−/− C57BL/6 donors were also significantly more susceptible to rejection than wild-type C57BL/6 grafts placed into BALB/c hosts, primarily as a result of increased T cell infiltration rather than enhanced priming. Taken together, our results identify differential roles for recipient vs donor PD-L1 in regulating induction vs effector of alloimmunity in corneal grafts, the most common form of tissue transplantation, and highlight the importance of peripheral tissue-derived PD-L1 in down-regulating local immune responses.

Dexamethasone, a synthetic corticosteroid, is widely used as a potent anti-inflammatory drug in various diseases including corneal angiogenesis. However, dexamethasone's impact on interleukin (IL)-1β-dependent inflammatory angiogenesis is unknown. Here, we show that dexamethasone inhibits IL-1β-induced neovascularization and the expression of the angiogenesis-related factors, vascular endothelial growth factor-A, KC, and prostaglandin E 2 in the mouse cornea 2 days after IL-1β implantation. IL-1β caused IκB-α phosphorylation in corneal stromal cells but not in infiltrated CD11b + cells 2 days after IL-1β implantation. In contrast, both cell types were positive for phosphorylated IκB-α 4 days after IL-1β implantation. Dexamethasone significantly inhibited IκB-α phosphorylation 2 and 4 days after IL-1β implantation. Furthermore, dexamethasone inhibited IL-1β-induced expression of vascular endothelial growth factor-A, KC, and prostaglandin E 2 , and signaling of nuclear factor (NF)-κB in corneal fibroblasts in vitro . A selective NF-κB inhibitor attenuated IL-1β-induced corneal angiogenesis. These findings suggest that NF-κB activation in the corneal stromal cells is an important early event during IL-1β-induced corneal angiogenesis and that dexamethasone inhibits IL-1β-induced angiogenesis partially via blocking NF-κB signaling.

We established a recessive cataract model from a spontaneous mutation in the KUNMING outbred mice. Lens opacity appears 11 days after birth. Slit lamp examination reveals that the opacity mainly localizes to the nuclear region of the lens. Histological analysis shows a severe degeneration of the epithelial cells underneath the anterior lens capsule, whereas those cells in the equatorial region display an excessive proliferation and migration. Within the cortical area underneath the posterior lens capsule, both vacuoles and morgagnian-like bodies are seen. Blue-stained spherical bodies are observed in the embryonic nucleus, forming a Y-like pattern. We mapped the disease locus and found a homozygous G to A nucleotide conversion at position 489 of Crygs in mutant mice, leading to a truncated gene product (Trp163Stop). This finding suggests that CRYGS is not only a lens structural protein, but is also likely to be involved in epithelial cell proliferation, apoptosis, and migration.

Purpose To analyze the effect of a resolvin D1 (RvD1) analogue (RvD1a) on dendritic cell maturation, T-cell sensitization, and allograft rejection in corneal allotransplantation. Methods The receptor expression of RvD1 (ALX/FPR2) on bone marrow-derived dendritic cells (BMDC) was measured using quantitative real-time PCR. We determined BMDC maturation after treatment with RvD1a using ELISA to measure interleukin (IL)-12 protein expression and flow cytometry to assess the expression of CD40, major histocompatibility complex (MHC) II, CD80, and CD86. After corneal transplantation in BALB/c mice, we analyzed T-cell infiltration in the cornea and the draining lymph nodes using flow cytometry. The enzyme-linked immunospot (ELISPOT) assay was used to measure T-cell sensitization via the direct and indirect pathway. Angiogenesis and lymphangiogenesis in the cornea after transplantation were measured using immunohistochemistry. Graft opacity and survival were evaluated by slit lamp biomicroscopy. Results The receptor for RvD1, lipoxin A4/formyl peptide receptor 2 (ALX/FPR2), was expressed at a significantly lower level on immature than mature dendritic cells (DCs), and RvD1a reduced DC expression of MHC II, CD40, and IL-12 following lipopolysaccharide (LPS) stimulation. Using a murine model of corneal transplantation, RvD1a-treated hosts exhibited significantly reduced allosensitization as demonstrated by decreased frequencies of interferon-gamma-secreting T cells in the draining lymph nodes, and reduced T-cell infiltration into the grafts. Graft survival was significantly enhanced and angiogenesis at the graft site was suppressed in RvD1a-treated hosts compared with vehicle-treated hosts. Conclusions These results suggest that RvD1 inhibits DC maturation and reduces alloimmune sensitization following transplantation, thereby establishing a novel connection between resolvin D1 and the regulation of DC-mediated, antigen-specific immunity.

To evaluate the correlation between changes in tear osmolarity, symptoms, and corneal fluorescein staining in patients with dry eye disease (DED).Retrospective, clinic-based cohort study.In this single-institution study, we reviewed the charts of 186 patients with DED from whom we had data on tear osmolarity, symptoms, and corneal fluorescein staining from 2 separate visits. Main outcomes included the correlation of the changes between the 2 visits for tear osmolarity (TearLab system), symptoms (Ocular Surface Disease Index), and corneal fluorescein staining (modified Oxford scheme). For tear osmolarity and corneal fluorescein staining the scores from the eye with highest readings were analyzed. The correlations were repeated on subgroups based on proposed cutoffs for DED severity and on patients' treatment.We found a modest, though statistically significant, correlation between changes in corneal fluorescein staining and symptoms of DED (R = 0.31; P.001). However, there was no correlation between the recorded change in tear osmolarity and symptoms (R = -0.091; P = .38) or between changes in tear osmolarity and corneal fluorescein staining (R = -0.02; P = .80). This lack of correlation was consistent in all the subgroups studied. A multivariate analysis revealed that changes in corneal fluorescein staining had predictive value on symptom changes, whereas tear osmolarity changes did not.Changes in tear osmolarity do not correlate significantly with changes in patient symptoms or corneal fluorescein staining in dry eye disease.

PURPOSE. Bone marrow–derived mesenchymal stem cells (MSCs) hold great promise for wound healing and tissue regeneration. In the present study, we investigated the impact of corneal injury on the homeostasis of endogenous MSCs, and the potential of MSCs to home to injured tissue and promote corneal repair. METHODS. Corneal injury in mice was induced by thermal cauterization. Circulating MSCs were quantified by flow cytometric analysis. Ex vivo expanded red Q-dot–labeled or GFPþ bone marrow–derived MSCs were intravenously injected after injury and detected using epifluorescence microscopy. Corneal fluorescein staining was performed to evaluate epithelial regeneration. RESULTS. Following the induction of corneal injury in mice, a 2fold increase in the frequency of circulating endogenous MSCs was observed within 48 hours of injury, which was accompanied by increased levels of the stem cell chemoattractants, substance P and SDF-1, in both the injured cornea and blood. Systemically administered MSCs homed to the injured cornea, but not to the normal cornea, and showed long-term survival. In addition, in the setting of corneal injury, MSC administration showed significant and rapid corneal epithelial regeneration. CONCLUSIONS. These findings provide novel evidence that corneal injury causes significant mobilization of endogenous MSCs into blood, and that MSCs home specifically to the injured cornea and promote regeneration, highlighting the therapeutic implications of MSC-mediated tissue repair in corneal injury. (Invest Ophthalmol Vis Sci. 2012;53:3638–3644) DOI:10.1167/ iovs.11-9311

Congenital cataracts cause 10–30% of all blindness in children, with one-third of cases estimated to have a genetic cause1. Lamellar cataract is the most common type of infantile cataract2. We carried out whole-genome linkage analysis of Chinese individuals with lamellar cataract, and found that the disorder is associated with inheritance of a 5.11-cM locus on chromosome 16. This locus coincides with one previously described for Marner cataract3. We screened individuals of three Chinese families for mutations in HSF4 (a gene at this locus that encodes heat-shock transcription factor 4) and discovered that in each family, a distinct missense mutation, predicted to affect the DNA-binding domain of the protein, segregates with the disorder. We also discovered an association between a missense mutation and Marner cataract in an extensive Danish family. We suggest that HSF4 is critical to lens development.

Th17 cells, in addition to their proinflammatory functions, have been recognized as potent inducers of angiogenesis in autoimmune diseases and malignancies. In the present study, we demonstrate distinct mechanisms by which IL-17 induces lymphangiogenesis. Using the mouse cornea micropocket and cell culture assays, our data demonstrate that IL-17 directly promotes growth of lymphatic vessels by inducing increased expression of prolymphangiogenic VEGF-D and proliferation of lymphatic endothelial cells. However, IL-17–induced growth of blood vessels is primarily mediated through IL-1β secretion by IL-17–responsive cells. Furthermore, in vivo blockade of IL-17 in a preclinical model of Th17-dominant autoimmune ocular disease demonstrates a significant reduction in the corneal lymphangiogenesis and in the progression of clinical disease. Taken together, our findings demonstrate a novel prolymphangiogenic function for Th17/IL-17, indicating that IL-17 can promote the progression and amplification of immunity in part through its induction of lymphangiogenesis.

(1R, 3R)-1-(1, 3-Benzodioxol-5-yl)-2-(chloroacetyl)-2, 3, 4, 9-tetrahydro-1H-pyrido[3, 4-b]indole-3-carboxylic acid methyl ester ((1R, 3R)-Cpe) is a key intermediate used in the synthesis of tadalafil, a highly selective phosphodiesterase type-5 inhibitor. In the present study, a chiral high-performance liquid chromatography method was developed for the simultaneous determination of diastereoisomeric and enantiomeric impurities in (1R, 3R)-Cpe. Separation was performed on an Ultron ES-OVM chiral column (150 mm × 4.6 mm, 5 μm,) with a guard column at a column temperature of 30°C. The gradient elution used was acetonitrile (solvent A) and water (solvent B), and the following elution program was used at a flow rate of 1 ml/min: 0–5 min (80% B), 5–10 min (80–60% B), 10–12 min (60% B). The detection wavelength was 220 nm. The four isomers of Cpe were baseline separated in 12 min. The results of method validation indicated that the method was specific and sensitive and was suitable for the quality control of diastereoisomeric and enantiomeric impurities in (1R, 3R)-Cpe. Chirality, 2012. © 2012 Wiley Periodicals, Inc.

Certain components of a graft that provoke alloimmunity may not be vital for graft function or critical as targets of rejection. Corneal transplantation is an example of this, because graft epithelium plays a role in allosensitization, whereas corneal graft endothelium-which shares the same alloantigens-is the critical target in allorejection. In this study, we found that exploiting this biology by replacing donor epithelium of an allograft with an allodisparate third-party epithelium yields a marked enhancement in transplant survival. Such 'chimeric' allografts consisted of a C3H/He (H-2(k)) corneal epithelium over a C57BL/6 (H-2(b)) epithelial-denuded cornea (or v.v.) and orthotopically placed on BALB/c (H-2(d)) hosts. Conventional corneal allografts (C3H/He or C57BL/6) or isografts (BALB/c) were also transplanted on BALB/c hosts. Alloreactive T-cell frequencies (CD4(+) interferon [IFN]-gamma(+)) primed to the graft endothelium were strongly diminished in chimeric hosts relative to conventionally allografted hosts. This was corroborated by a decreased T-cell infiltration (p = 0.03) and a marked enhancement of allograft survival (p = 0.001). Our results represent the first successful demonstration of chimeric tissue, epithelial-denuded allograft plus third-party allodisparate epithelium, in the promotion of allograft survival. Moreover, chimeric grafting can be readily performed clinically, whereby corneal allograft rejection remains a significant problem particularly in inflamed graft beds.

Vascular endothelial growth factor receptor (VEGFR)-2 is a major stimulator of hemangiogenesis (HA), whereas VEGFR-3 stimulates lymphangiogenesis (LA). Contrary to this understanding, we demonstrate that implantation of pellets containing VEGFR-3-specific ligands (VEGF-C156S and recombinant murine VEGF-D) into the corneal stroma induce not only LA but also robust HA characterized by blood vessels that are positive for VEGFR-3 expression. The implantation of pellets containing VEGFR-3-specific ligands also leads to the recruitment of VEGF-A-secreting macrophages. Depletion of these infiltrating macrophages using clodronate-liposome administration shows a significant reduction in HA as well as LA. Blockade of either VEGFR-2 or VEGFR-3 signaling reduces both HA and LA; however, the percent reduction of HA is greater in the VEGFR-2 blockade group. In addition, in the VEGFR-3 blockade group, the percent reduction of RA is significantly greater with VEGFR-3-specific ligands than that by VEGF-A or VEGF-C. Collectively, our data suggest that VEGFR-3-specific signaling can induce new blood vessels, to which macrophages contribute a major role, and signify its potential as an additional therapeutic target to the existing VEGF-A/VEGFR-2 signaling-based antiangiogenesis strategies. (Am J Pathol 2009, 175:1984-1992; DOI: 10.2353/ajpath.2009.080515)

Dexamethasone, a synthetic corticosteroid, is widely used as a potent anti-inflammatory drug in various diseases including corneal angiogenesis. However, dexamethasone's impact on interleukin (IL)-1beta-dependent inflammatory angiogenesis is unknown. Here, we show that dexamethasone inhibits IL-1beta-induced neovascularization and the expression of the angiogenesis-related factors, vascular endothelial growth factor-A, KC, and prostaglandin E(2) in the mouse cornea 2 days after IL-1beta implantation. IL-1beta caused IkappaB-alpha phosphorylation in corneal stromal cells but not in infiltrated CD11b(+) cells 2 days after IL-1beta implantation. In contrast, both cell types were positive for phosphorylated IkappaB-alpha 4 days after IL-1beta implantation. Dexamethasone significantly inhibited IkappaB-alpha phosphorylation 2 and 4 days after IL-1beta implantation. Furthermore, dexamethasone inhibited IL-1beta-induced expression of vascular endothelial growth factor-A, KC, and prostaglandin E(2), and signaling of nuclear factor (NF)-kappaB in corneal fibroblasts in vitro. A selective NF-kappaB inhibitor attenuated IL-1beta-induced corneal angiogenesis. These findings suggest that NF-kappaB activation in the corneal stromal cells is an important early event during IL-1beta-induced corneal angiogenesis and that dexamethasone inhibits IL-1beta-induced angiogenesis partially via blocking NF-kappaB signaling.