Search

Regulatory T (T

In the present work, 316L stainless steel specimens are fabricated by selective laser melting (SLM) via optimized laser process parameters. The effects of two extrinsic factors, i.e., strain rate and annealing temperature, on the mechanical performance of SLM-processed parts are studied. The two intrinsic factors, namely strain rate sensitivity m and work hardening exponent n, which control the tensile properties of the as-built samples, are quantified. Microstructure characterizations show that cellular structure and crystalline grain exhibit apparently different thermal stability at 873 K. Tensile testing reveals that the yield strength decreases from 584 ± 16 MPa to 323 ± 2 MPa, while the elongation to failure increases from (46 ± 1)% to (65 ± 2)% when annealing temperature varies from 298 K to 1328 K. The n value increases from 0.13 to 0.33 with the increase in annealing temperature. Due to the presence of fine cellular structures and high relative density achieved in as-printed 316L samples, a strong dependence between tensile yield strength and strain rate is observed. In addition, the strain rate sensitivity of the SLM-produced 316L part (m = 0.017) is much larger than that of conventional coarse-grained part (m = 0.006), whereas the n value increases slightly from 0.097 to 0.14 with increasing strain rate.

Background Clear aligner (CA) treatment has been gaining popularity, but the biomechanical effects of CAs in bimaxillary dentition have not been thoroughly investigated. Direct and indirect strong anchorages are two common anchorage control methods, but the underlying biomechanical mechanism has not yet been elucidated. This study aimed to investigate the different biomechanical effects of CAs in closing the bimaxillary space under different anchorage controls, further instructing the compensation strategies design and strong anchorage choice in clinical practice. Methods Three-dimensional (3D) bimaxillary models of different anchorage controls were created based on cone-beam computed tomography and intraoral scan data. Four first premolars were extracted using 3D modeling software. Finite element analysis was conducted to simulate the space closure process of the CAs. Results In the two strong anchorage groups, the bimaxillary dentition presented different movement patterns during the space closure process, and the lower dentition was more vulnerable to elastic force. From the vertical view, direct strong anchorage with elastic force had the advantage of flattening the longitudinal occlusal curve and resisting the roller-coaster effects, whereas indirect strong anchorage could lead to a deep longitudinal occlusal curve. From the sagittal view, indirect strong anchorage with metallic ligaments had a greater instantaneous anchorage protection effect, particularly in the lower dentition, which reduced the mesial movement of the posterior teeth by nearly four times that of the direct anchorage group. In addition, indirect strong anchorage presented better anterior teeth torque/tipping control, while direct strong anchorage could aggravate lingual tipping of the upper central incisors. Due to the differences in anterior–posterior anchorage and arch shape, compared with the upper dentition, anchorage preservation and vertical control effects were amplified in the lower dentition. Conclusions The biomechanical effects of CAs differed between the two strong anchorage groups. Due to the differences in dentition morphology, anterior–posterior anchorage, and dental arch shape, CAs present different biomechanical effects in bimaxillary space closure. Orthodontists should consider the corresponding mechanical compensation according to specific anchorage control methods and dentitions.

During early mammalian embryogenesis, changes in cell growth and proliferation depend on strict genetic and metabolic instructions. However, our understanding of metabolic reprogramming and its influence on epigenetic regulation in early embryo development remains elusive. Here we show a comprehensive metabolomics profiling of key stages in mouse early development and the two-cell and blastocyst embryos, and we reconstructed the metabolic landscape through the transition from totipotency to pluripotency. Our integrated metabolomics and transcriptomics analysis shows that while two-cell embryos favour methionine, polyamine and glutathione metabolism and stay in a more reductive state, blastocyst embryos have higher metabolites related to the mitochondrial tricarboxylic acid cycle, and present a more oxidative state. Moreover, we identify a reciprocal relationship between α-ketoglutarate (α-KG) and the competitive inhibitor of α-KG-dependent dioxygenases, L-2-hydroxyglutarate (L-2-HG), where two-cell embryos inherited from oocytes and one-cell zygotes display higher L-2-HG, whereas blastocysts show higher α-KG. Lastly, increasing 2-HG availability impedes erasure of global histone methylation markers after fertilization. Together, our data demonstrate dynamic and interconnected metabolic, transcriptional and epigenetic network remodelling during early mouse embryo development.

Zika virus (ZIKV) infection during pregnancy can cause microcephaly in newborns, yet the underlying mechanisms remain largely unexplored. Here, we reveal extensive and large-scale metabolic reprogramming events in ZIKV-infected mouse brains by performing a multi-omics study comprising transcriptomics, proteomics, phosphoproteomics and metabolomics approaches. Our proteomics and metabolomics analyses uncover dramatic alteration of nicotinamide adenine dinucleotide (NAD+)-related metabolic pathways, including oxidative phosphorylation, TCA cycle and tryptophan metabolism. Phosphoproteomics analysis indicates that MAPK and cyclic GMP-protein kinase G signaling may be associated with ZIKV-induced microcephaly. Notably, we demonstrate the utility of our rich multi-omics datasets with follow-up in vivo experiments, which confirm that boosting NAD+ by NAD+ or nicotinamide riboside supplementation alleviates cell death and increases cortex thickness in ZIKV-infected mouse brains. Nicotinamide riboside supplementation increases the brain and body weight as well as improves the survival in ZIKV-infected mice. Our study provides a comprehensive resource of biological data to support future investigations of ZIKV-induced microcephaly and demonstrates that metabolic alterations can be potentially exploited for developing therapeutic strategies.

Background Prostaglandin analogs (PGAs) are the first-line treatment for primary open-angle glaucoma (POAG) and ocular hypertension (OH). This study aimed to confirm the effectiveness and safety of Tapros® (0.0015% tafluprost eye drops) in Chinese patients with POAG and OH. Methods This phase IV, multicenter, non-comparative, prospective study enrolled patients with POAG and OH in China between 12/27/2017 and 04/15/2020. Patients who were treatment-naïve or untreated within one month (group A) or with unreached intraocular pressure (IOP) target after previous monotherapy of other PGAs (group B) or non-PGA IOP-lowering drugs (group C) were treated with 0.0015% tafluprost for three months. The IOP reduction, response rate, and safety were observed. Results There were 165, 89, and 31 patients in groups A, B, and C, with baseline IOPs of 22.4 ± 4.7, 21.0 ± 3.5, and 22.5 ± 3.2 mmHg, respectively. The least-square means and percentages of IOP reduction at 3 months for groups A, B, and C were 4.7 (19.8%), 1.6 (6.1%), and 4.6 mmHg (20.3%), respectively. A significant reduction in IOP was observed at each visit compared with baseline (all P Conclusions Tafluprost showed a sustained and significant effect with tolerable adverse events in Chinese patients with POAG and OH who were treatment-naïve or untreated within one month or received prior treatments with unsatisfying outcomes.

Ocular infection induced by bacteria and fungi is a major cause of visual impairment and blindness. Topical administration of antibiotics remains the first-line treatment, as effective eradication of pathogens is the core of the anti-infection strategy. Whereas, eye drops lack efficiency and have relatively low bioavailability. Intraocular injection may cause concurrent ocular damage and secondary infection. In addition, antibiotic-based management can be limited by the low sensitivity to multidrug-resistant bacteria. Nanomedicine is proposed as a prospective, effective, and noninvasive platform to mediate ocular delivery and combat pathogen or even resistant strains. Nanomedicine can not only carry antimicrobial agents to fight against pathogens but also directly active microbicidal capability, killing pathogens. More importantly, by modification, nanomedicine can achieve enhanced residence time and release time on the cornea, and easy penetration through corneal tissues into anterior and posterior segments of the eye, thus improving the therapeutic effect for ocular infection. In this review, several categories of antimicrobial nanomedicine are systematically discussed, where the efficiency and possibility of further embellishment and improvement to adapt to clinical use are also investigated. All in all, novel antimicrobial nanomedicine provides potent and prospective ways to manage severe and refractory ocular infections.

The age-dependent decline in remyelination potential of the central nervous system during ageing is associated with a declined differentiation capacity of oligodendrocyte progenitor cells (OPCs). The molecular players that can enhance OPC differentiation or rejuvenate OPCs are unclear. Here we show that, in mouse OPCs, nuclear entry of SIRT2 is impaired and NAD+ levels are reduced during ageing. When we supplement β-nicotinamide mononucleotide (β-NMN), an NAD+ precursor, nuclear entry of SIRT2 in OPCs, OPC differentiation, and remyelination were rescued in aged animals. We show that the effects on myelination are mediated via the NAD+-SIRT2-H3K18Ac-ID4 axis, and SIRT2 is required for rejuvenating OPCs. Our results show that SIRT2 and NAD+ levels rescue the aged OPC differentiation potential to levels comparable to young age, providing potential targets to enhance remyelination during ageing.

Antibiotic resistance is an increasingly serious threat to global public health, which can lead to the decrease of the effectiveness of antibiotics. The combination therapy of antibiotic and mild temperature photothermal therapy (PTT) is adopted to address this issue in this work. An antibiotic-loaded nanoplatform is fabricated based on two-dimensional (2D) molybdenum disulfide (MoS2) nanoflakes as effective near-infrared (NIR) photothermal agent. The MoS2 nanoflakes is modified with positively charged quaternized chitosan (QCS) to improve the dispersion stability and enhance the interaction between MoS2 nanoflakes and bacterial membrane. The QCS modified MoS2 nanoflakes (QCS-MoS2) is expected to adhere onto the membrane of methicillin-resistant Staphylococcus aureus (MRSA) and depolarize the bacterial membrane by local hyperthermia under NIR irradiation. A first-line antibiotic, ofloxacin (OFLX), can be loaded onto QCS-MoS2 by π-π stacking and hydrophobic interaction. Due to the combined antibiotic-photothermal therapy, superior bactericidal ability was achieved at mild temperature (45 °C) and low antibiotic concentration. Such synergistic mild-temperature photothermal/antibiotic therapy can not only avoid the damage to neighboring tissue by PTT, but also reduce the development of drug resistance, providing an innovative way for the treatment of bacterial infections.

Nonmelanoma skin cancer (NMSC) such as cutaneous squamous cell carcinoma (cSCC) is caused by solar ultraviolet (SUV) exposure and is the most common cancer in the United States. T-LAK cell-originated protein kinase (TOPK), a serine-threonine kinase is activated by SUV irradiation and involved in skin carcinogenesis. Strategies with research focusing on the TOPK signaling pathway and targeted therapy in skin carcinogenesis may helpful for the discovery of additional treatments against skin cancer. In this study, we found that TOPK can directly bind to and phosphorylate c-Jun (as one of the core member of AP-1) at Ser63 and Ser73 after SSL exposure in a JNKs-independent manner. TOPK knocking down, or HI-TOPK-032 (TOPK specific inhibitor) attenuated colony formation and cell proliferation of skin cancer cells. Phosphorylated levels of c-Jun were overexpressed in human AK and cSCC compared with normal skin tissues, and HI-TOPK-032 inhibited the phosphorylation of c-Jun in SCC cell line in a dose-dependent manner. Furthermore, HI-TOPK-032 decreased SSL-induced AP-1 transactivation activity. Moreover, acute SSL-induced inflammation was attenuated by the topical application of HI-TOPK-032 in SKH1 hairless mice. Importantly, HI-TOPK-032 suppressed chronic SSL-induced skin carcinogenesis and c-Jun phosphorylation levels in SKH1 hairless mice. Our results demonstrate that TOPK can phosphorylate and activate c-Jun at Ser63 and Ser73 in the process of skin carcinogenesis and HI-TOPK-032 could be used as a potential chemopreventive drug against cSCC development.

Dysregulation of PARP10 has been implicated in various tumor types and plays a vital role in delaying hepatocellular carcinoma (HCC) progression. However, the mechanisms controlling the expression and activity of PARP10 in HCC remain mostly unknown. The crosstalk between PLK1, PARP10, and NF-κB pathway in HCC was determined by performing different in vitro and in vivo assays, including mass spectrometry, kinase, MARylation, chromatin immunoprecipitation, and luciferase reporter measurements. Functional examination was performed by using small chemical drug, cell culture, and mice HCC models. Correlation between PLK1, NF-κB, and PARP10 expression was determined by analyzing clinical samples of HCC patients with using immunohistochemistry. PLK1, an important regulator for cell mitosis, directly interacts with and phosphorylates PARP10 at T601. PARP10 phosphorylation at T601 significantly decreases its binding to NEMO and disrupts its inhibition to NEMO ubiquitination, thereby enhancing the transcription activity of NF-κB toward multiple target genes and promoting HCC development. In turn, NF-κB transcriptionally inhibits the PARP10 promoter activity and leads to its downregulation in HCC. Interestingly, PLK1 is mono-ADP-ribosylated by PARP10 and the MARylation of PLK1 significantly inhibits its kinase activity and oncogenic function in HCC. Clinically, the expression levels of PLK1 and phosphor-p65 show an inverse correlation with PARP10 expression in human HCC tissues. These findings are the first to uncover a PLK1/PARP10/NF-κB signaling circuit that underlies tumorigenesis and validate PLK1 inhibitors, alone or with NF-κB antagonists, as potential effective therapeutics for PARP10-expressing HCC.

To automatically detect and classify the lesions of diabetic retinopathy (DR) in fundus fluorescein angiography (FFA) images using deep learning algorithm through comparing 3 convolutional neural networks (CNNs). A total of 4067 FFA images from Eye Center at the Second Affiliated Hospital of Zhejiang University School of Medicine were annotated with 4 kinds of lesions of DR, including non-perfusion regions (NP), microaneurysms, leakages, and laser scars. Three CNNs including DenseNet, ResNet50, and VGG16 were trained to achieve multi-label classification, which means the algorithms could identify 4 retinal lesions above at the same time. The area under the curve (AUC) of DenseNet reached 0.8703, 0.9435, 0.9647, and 0.9653 for detecting NP, microaneurysms, leakages, and laser scars, respectively. For ResNet50, AUC was 0.8140 for NP, 0.9097 for microaneurysms, 0.9585 for leakages, and 0.9115 for laser scars. And for VGG16, AUC was 0.7125 for NP, 0.5569 for microaneurysms, 0.9177 for leakages, and 0.8537 for laser scars. Experimental results demonstrate that DenseNet is a suitable model to automatically detect and distinguish retinal lesions in the FFA images with multi-label classification, which lies the foundation of automatic analysis for FFA images and comprehensive diagnosis and treatment decision-making for DR.

Background Trophoblast dysfunction during pregnancy is fundamentally involved in preeclampsia. Several studies have revealed that human chorionic villous mesenchymal stem cells (CV-MSCs) could regulate trophoblasts function. Results To understand how human chorionic villous mesenchymal stem cells (CV-MSCs) regulate trophoblast function, we treated trophoblasts with CV-MSC supernatant under hypoxic conditions. Treatment markedly enhanced proliferation and invasion and augmented autophagy. Transcriptome and pathway analyses of trophoblasts before and after treatment revealed JAK2/STAT3 signalling as an upstream regulator. In addition, STAT3 mRNA and protein levels increased during CV-MSC treatment. Consistent with these findings, JAK2/STAT3 signalling inhibition reduced the autophagy, survival and invasion of trophoblasts, even in the presence of CV-MSCs, and blocking autophagy did not affect STAT3 activation in trophoblasts treated with CV-MSCs. Importantly, STAT3 overexpression increased autophagy levels in trophoblasts; thus, it positively regulated autophagy in hypoxic trophoblasts. Human placental explants also proved our findings by showing that STAT3 was activated and that LC3B-II levels were increased by CV-MSC treatment. Conclusion In summary, our data suggest that CV-MSC-dependent JAK2/STAT3 signalling activation is a prerequisite for autophagy upregulation in trophoblasts. Graphic abstract

In the process of exploring new methods for cataract treatment, lens regeneration is an ideal strategy for effectively restoring accommodative vision and avoiding postoperative complications and has great clinical potential. Lens regeneration, which is not a simple repetition of lens development, depends on the complex regulatory network comprising the FGF, BMP/TGF-β, Notch, and Wnt signaling pathways. Current research mainly focuses on in situ and in vitro lens regeneration. On the one hand, the possibility of the autologous stem cell in situ regeneration of functional lenses has been confirmed; on the other hand, both embryonic stem cells and induced pluripotent stem cells have been induced into lentoid bodies in vitro which are similar to the natural lens to a certain extent. This article will briefly summarize the regulatory mechanisms of lens development, describe the recent progress of lens regeneration, explore the key molecular signaling pathways, and, more importantly, discuss the prospects and challenges of their clinical applications to provide reference for clinical transformations.

Inflammation is a complex biological host reaction to tissue damage, infection and trauma. Extensive study of the inflammatory response has led to the identification of several protein kinases that are essential for signaling and could be potential therapeutic targets. The RSK family of kinases has multiple cellular functions. In our study, we found that RSK2 is a mediator for inflammation signaling and interacts with TRAF6. In vitro kinase assay results indicated that RSK2 strongly phosphorylates TRAF6 at serines 46, 47 and 48. Ectopic overexpression of TRAF6 or knocking down RSK2 expression confirmed that RSK2 is a positive regulator of TRAF6 K63 ubiquitination. TRAF6 is also required for RSK2 ubiquitination. TRAF6 bridges the TNF receptor superfamily and intracellular signaling for the induction of proinflammatory cytokines. We developed a colon inflammation model using RSK2 wild type (WT) and knockout (KO) mice. As expected, F4/80 and CD3 infiltration were significantly upregulated in WT mice compared to RSK2 KO mice. Furthermore, inflammation signaling, including Ikkα/β, p38 and JNKs, was dramatically upregulated in WT mice. Colon tissue immunoprecipitation results further confirmed that TRAF6 K63 ubiquitination was lower in RSK2 KO mice. Overall, these results indicate that phosphorylation of TRAF6 (S46, 47, 48) by RSK2 is required for TRAF6 K63 ubiquitination and inflammation signaling.

Development of a simple and rapid method for the preparation of cellulose/ZnO composites is of great importance for broadening and improving their potential applications. In this work, the cellulose/ZnO composites were synthesized via the microwave-assisted hydrothermal method using cellulose, zinc nitrate hexahydrate, and ammonia in an aqueous solution. The influence of the cellulose on ZnO crystals was investigated in detail. Cell cytotoxicity of the as-obtained cellulose/ZnO composites was explored. All the cell viability values of the cellulose/ZnO composites were above 95%, indicating that cellulose/ZnO composites had essentially no cytotoxicity. ZnO/carbon (ZnO/C) composites were obtained by calcination at 600 °C in the N2 atmosphere using cellulose/ZnO composites as precursors. The flower-shaped ZnO crystals could still maintain their morphologies via the N2 atmosphere calcination. These ZnO/C composites exhibited good photocatalytic performances under both UV and visible light irradiation. Under the UV light irradiation, the degradation efficiency values of methylene blue and rhodamine B dyes were up to 99% and 97%, respectively. The kinetic linear model curves of the photocatalytic degradation of the two dyes could be assigned to the pseudo-first-order kinetics model. This work provided a potential strategy for the synthesis of metallic oxide/cellulose composites, which have broadened the applications of the composites.

The surface damage performance of fused silica under mono-wavelength configuration or simultaneous dual-wavelength exposures to 1053, 527, and 351 nm nanosecond-laser pulses is investigated in order to probe the mechanisms governing damage initiation during frequency conversion. Based on the absorption and heat transfer mechanism, coupled to laser damage statistics, a model considering the Gaussian distribution of irradiation intensity has been presented to obtain precise calculation result about laser damage probability. Laser damage probability curves are measured on the surface of fused silica with different wavelength configurations. By studying the influence of the laser wavelength configurations on the laser damage probability, we show with our methodology that the types of damage precursors under the irradiation of different wavelength configurations can be identified.

To assess the visual effects of trifocal intraocular lenses (IOLs) compared to bifocal IOLs in cataract surgery, a meta-analysis of prospective comparative clinical trials (including 4 randomized controlled trials and 4 cohorts) was conducted. The defocus curves showed a better distance-corrected intermediate visual acuity (VA) for the trifocal group (MD −0.07; 95% CI, −0.10 to −0.05; p p = 0.13 for uncorrected distance VA and MD −0.00; 95% CI, −0.01 to 0.01; p = 0.78 for distance-corrected distance VA), near VA (MD −0.01; 95% CI, −0.07 to 0.04; p = 0.68 for uncorrected near VA and MD −0.01; 95% CI, −0.06 to 0.04; p = 0.66 for distance-corrected near VA) or refraction between the two groups. Contrast sensitivity and subjective visual quality yielded less conclusive results. Overall, a patient may achieve better intermediate VA with a trifocal IOL than with a bifocal IOL without any adverse effect on distance or near VA. The findings on contrast sensitivity and subjective visual quality were heterogeneous, with no clear results favoring either option.

Endophthalmitis can be a devastating complication after cataract surgery. Therefore, this study sought to better understand the occurrence rate of acute-onset postoperative endophthalmitis after cataract surgery in Chinese small and medium-scale departments of ophthalmology, as well as identify its risk factors and assess the treatment options. This investigation revealed 52 postoperative endophthalmitis cases in 46,185 operations at 30 hospitals from 2011 to 2013, at an occurrence rate of 0.11%. A small cataract surgery volume of less than 500 cases per year (OR 2.21; p = 0.006), the absence of 0.5% povidone iodine (PVP-I) irrigation (OR 1.73; p = 0.046), and intraoperative posterior capsular rupture (PCR) with vitreous loss (OR 4.40; p = 0.034) showed statistically significant associations with endophthalmitis in the multivariate analysis. The rate of culture positivity was 44.2%, with Staphylococcus epidermidis being the most common organism isolated in China. More than 40% of the endophthalmitis cases were treated with a nonstandard antibiotics regimen, and only 32.7% of these had a visual acuity of better than 20/40. We concluded that the occurrence rate of acute-onset endophthalmitis following cataract surgery in Chinese small and medium-scale departments of ophthalmology lags behind the level of developed countries, as well as Chinese top eye centers. Overall, the use of 0.5% PVP-I irrigation seemed to be an effective measure to reduce the risk of the development of postoperative endophthalmitis.

Evaporative cooling of singly charged ions in a Penning trap is studied. The ions are created by in-situ electron bombardment of hydrogen molecules and trapped in a cylindrical Penning trap. Cooling of the ions is observed by their axial motion after trapping of a few hundred milliseconds. The ions temperature decreases by a factor of more than 6 in 800 ms, while the bunch density of the coldest ions increases by up to a factor of 10. By studying the time constants of the dependence of ion loss and axial temperature on the magnetic field strength, we exclude the effects of ions loss through the cyclotron motion on the axial ion temperature.

To investigate the morphological characteristics of myopic macular retinoschisis (MRS) in teenagers with high myopia, six male (9 eyes) and 3 female (4 eyes) teenagers with typical MRS identified from chart review were evaluated. All cases underwent complete ophthalmic examinations including best corrected visual acuity (BCVA), indirect ophthalmoscopy, colour fundus photography, B-type ultrasonography, axial length measurement and spectral-domain optical coherence tomography (SD-OCT). The average age was 17.8 ± 1.5 years, average refractive error was −17.04 ± 3.04D, average BCVA was 0.43 ± 0.61 and average axial length was 30.42 ± 1.71 mm. Myopic macular degenerative changes (MDC) by colour fundus photographs revealed Ohno-Matsui Category 1 in 4 eyes and Category 2 in 9 eyes. Posterior staphyloma was found in 9 eyes. SD-OCT showed outer MRS in all 13 eyes, internal limiting membrane detachment in 7 eyes, vascular microfolds in 2 eyes and inner MRS in 1 eye. No premacular structures such as macular epiretinal membrane or partially detached posterior hyaloids were found. Our results showed that MRS rarely occurred in highly myopic teenagers and was not accompanied by premacular structures, severe MDC, or even obvious posterior staphyloma. This finding indicates that posterior scleral expansion is probably the main cause of MRS.

Autosomal dominant congenital cataracts (ADCC) are clinically and genetically heterogeneous diseases. The present study recruited two Chinese families with bilateral nuclear cataract or zonular pulverulent phenotype. Direct sequencing of candidate genes identified two novel missense mutations of Cx50, Cx50P59A (c.175C > G) and Cx50R76H (c.227G > A), both co-segregated well with all affected individuals. Bioinformatics analysis predicted deleterious for both mutations. Functional and cellular behaviors of wild type and mutant Cx50 examined by stably transfecting recombinant systems revealed similar protein expression levels. Protein distribution pattern by fluorescence microscopy showed that Cx50R76H localized at appositional membranes forming gap junctions with enormous cytoplasmic protein accumulation, whereas the Cx50P59A mutation was found inefficient at forming detectable plaques. Cell growth test by MTT assay showed that induction of Cx50P59A decreased cell viability. Our study constitutes the first report that the Cx50P59A and Cx50R76H mutations are associated with ADCC and expands the mutation spectrum of Cx50 in association with congenital cataracts. The genetic, cellular, and functional data suggest that the altered intercellular communication governed by mutated Cx50 proteins may act as the molecular mechanism underlying ADCC, which further confirms the role of Cx50 in the maintenance of human lens transparency.

Rapid and adequate vascularization is vital to the long-term success of porous orbital enucleation implants. In this study, porous hydroxyapatite (HA) scaffolds coated with vascular endothelial growth factor (VEGF)-functionalized collagen (COL)/heparin (HEP) multilayers (porosity 75%, pore size 316.8 ± 77.1 μm, VEGF dose 3.39 ng/mm3) were fabricated to enhance vascularization by inducing the differentiation of mesenchymal stem cells (MSCs) to endothelial cells. The in vitro immunofluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting results demonstrated that the expression of the endothelial differentiation markers CD31, Flk-1 and von Willebrand factor (vWF) was significantly increased in the HA/(COL/HEP)5/VEGF/MSCs group compared with the HA/VEGF/MSCs group. Moreover, the HA/(COL/HEP)5 scaffolds showed a better entrapment of the MSCs and accelerated cell proliferation. The in vivo assays showed that the number of newly formed vessels within the constructs after 28 d was significantly higher in the HA/(COL/HEP)5/VEGF/MSCs group (51.9 ± 6.3/mm2) than in the HA (26.7 ± 2.3/mm2) and HA/VEGF/MSCs (38.2 ± 2.4/mm2) groups. The qRT-PCR and western blotting results demonstrated that the HA/(COL/HEP)5/VEGF/MSCs group also had the highest expression of CD31, Flk-1 and vWF at both the mRNA and protein levels.

Understanding and controlling the mechanism by which stem cells balance self-renewal versus differentiation is of great importance for stem cell therapeutics. Klf4 promotes the self-renewal of embryonic stem cells, but the precise mechanism regulating this role of Klf4 is unclear. We found that ERK1 or ERK2 binds the activation domain of Klf4 and directly phosphorylates Klf4 at Ser123. This phosphorylation suppresses Klf4 activity, inducing embryonic stem cell differentiation. Conversely, inhibition of Klf4 phosphorylation enhances Klf4 activity and suppresses embryonic stem cell differentiation. Notably, phosphorylation of Klf4 by ERKs causes recruitment and binding of the F-box proteins βTrCP1 or βTrCP2 (components of an ubiquitin E3 ligase) to the Klf4 N-terminal domain, which results in Klf4 ubiquitination and degradation. Overall, our data provide a molecular basis for the role of ERK1 and ERK2 in regulating Klf4-mediated mouse embryonic stem cell self-renewal.

To evaluate the morphological changes that occurred during the development of a full-thickness macular hole (FTMH) from macular retinoschisis (MRS) in highly myopic eyes by optical coherence tomography (OCT). The clinical characteristics and OCT images of five eyes of five patients with myopic MRS who developed FTMH during the follow-up period were evaluated. The natural evolution from MRS to FTMH was classified into two patterns by OCT findings. In FTMH formation pattern 1, a focal area of the external retinal layer was elevated and followed by the development of a small outer lamellar macular hole (OLMH) and retinal detachment (RD). The OLMH and RD were then enlarged horizontally and elevated vertically until the OLMH was attached to the overlying retinal layer. A FTMH finally developed when the roof of RD opened. In FTMH formation pattern 2, the opening of the roof of MRS or cystoid space caused an inner lamellar macular hole (ILMH). The MRS was then gradually resolved except the residual MRS beneath the ILMH, the ILMH would finally proceed into a FTMH as long as the remained external retinal layer beneath the ILMH continued splitting posteriorly until it reached retinal epithelium pigment. Our longitudinal study revealed two patterns of FTMH formation in highly myopic eyes with MRS. This finding might be useful in further understanding the pathogenesis of macular hole formation in high myopia.

To objectively assess the effect of Qiming Granule (芪明颗粒) in the treatment of diabetic retinopathy (DR) by fluorescence fundus angiography (FFA). In a multi-center, randomized, parallel controlled clinical trial, patients with DR were randomly assigned to the control group (calcium dobesilate capsule) and the test group (Qiming Granule). Changes in the retinal blood circulation time were recorded by FFA after 3 months of medication. Significant reduction was observed in the retinal arterio-venous circulation time (AVCT) in both groups (P 0.05) respectively. The ARCT in the tested group was reduced, with a statistically significant difference post-medication (P

Surface modification with dielectric barrier discharge (DBD) plasma was carried out at atmospheric pressure (argon as the discharge gas) to improve the biocompatibility of hydrophobic acrylate intraocular lens (IOL). Changes of the plasma-treated IOL surface in chemical composition, morphology and hydrophilicity were comprehensively evaluated by X-ray photoelectron spectroscopy (XPS), field emission scanning electron microscopy (FESEM), atomic force microscopy (AFM) and water contact angle (WCA) measurements. The surface biocompatibility of the untreated and plasma-treated IOLs was compared with the adhesion behavior of platelets, macrophages and lens epithelial cells (LECs) in vitro. After DBD plasma treatment, the hydrophilicity of the IOL surface was obviously improved. The changes in WCA with treatment extension may be attributed to both the introduction of oxygen or/and nitrogen-containing polar groups and the increase of surface roughness induced by plasma etching effect. The existence of low molecular weight oxidized material (LMWOM) was proved on the plasmatreated IOL which was caused by the chain scission effect of the plasma treatment. The plasma-treated IOLs resisted the adhesion of platelets and macrophages significantly. The LECs spreading and proliferation were postponed on the IOLs plasma-treated for more than 180 s, with a well maintained epithelial phenotype of LECs. The IOL biocompatibility was improved after the DBD plasma treatment. We speculate that slighter foreign-body reaction and later incidence of anterior capsule opacification (ACO) may be expected after implantation of the argon DBD plasma-treated IOL.

To determine the effectiveness of staining an epiretinal membrane (ERM) with triamicinolone acedonide (TA) during vitrectomy for a retinal detachment (RD) due to a macular hole (MH) in highly myopic eyes.Thirty-four highly myopic eyes (-6.0 dioptres) of 34 patients with an RD caused by an MH underwent vitrectomy with TA-assisted ERM removal. The excised ERMs from five eyes were examined by transmission electron microscopy (TEM). The main outcome measures were the retinal status and best-corrected visual acuity (BCVA). The anatomic status of the MH was determined by optic coherence tomography (OCT) in 24 successfully retinal-reattached eyes. The follow-up periods ranged from 5 to 20 months.The granules of TA adhered to the ERM and the residual posterior hyaloid, which made them more visible and facilitated their removal. Tissues resembling the internal limiting membrane were not detected in any of the five excised tissues. The retinal reattachment rate was 88% after the first surgery. The mean log MAR BCVA significantly improved from 1.83+/-0.50 (mean+/-SD) before surgery to 1.22+/-0.35 at the final follow-up (P0.001, Wilcoxon signed rank test). OCT showed a normal concave appearance in 11 of 24 eyes (46%), but a central neural epithelial defect was present in 13 of 24 eyes (54%).TA facilitates the complete removal of both the ERM and residual posterior hyaloid, thus ensuring high anatomical and visual success rates in highly myopic eyes with an RD due to MH.

To determine whether bone marrow-derived progenitor cells can be stimulated by inflammatory mediators and play a role in corneal wound healing following alkali injury. Sixty rabbits were divided into two groups( Group I and Group II). Group I served as a bone marrow-suppression model, and received 200 mg/kg cyclophosphamide. Corneal alkali injury was created in one eye of each rabbit in each group; the other eye served as control. Three days after corneal burn, inflammatory cells in peripheral blood were counted. At the end of 4 weeks follow-up, corneas of all rabbits were subjected to histochemical examination to assess infiltrated CD34 and C-kit positive cells. Clinical outcome was determined at the end of 4 weeks. Cyclophosphamide suppressed bone marrow function in Group I by reducing cellularity by more than 30% and neutrophil distribution by 3.18 ± 1.83%. The number of bone marrow hematopoietic and mesenchymal progenitor cells were all suppressed by cyclophophamide, as demonstrated by statistically significant differences between Group I and Group II of CD34+ cells (t = −21.62, P

To study proteomic changes in human lens epithelial cells (HLECs) exposed to 1800-MHz Global System for Mobile Communication (GSM)-like microwaves. In three separate experiments, HLECs were exposed and sham-exposed (six dishes each) to 1800-MHz GSM-like radiation for 2 h. The specific absorption rates were 1.0, 2.0, or 3.5 W/kg. Immediately after radiation, the proteome was extracted from the HLECs. Immobilized pH gradient two-dimensional polyacrylamide gel electrophoresis(2-DE; silver staining) and PDQuest 2-DE analysis software were used to separate and analyze the proteome of exposed and sham-exposed HLECs. Four differentially expressed protein spots were selected and identified by using electrospray ionization tandem mass spectrometry (ESI-MS-MS). When the protein profiles of exposed cells were compared with those of sham-exposed cells, four proteins were detected as upregulated. After analysis by ESI-MS-MS and through a database search, heat-shock protein (HSP) 70 and heterogeneous nuclear ribonucleoprotein K (hnRNP K) were determined to be upregulated in the exposed cells. Two-dimensional polyacrylamide gel electrophoresis combined with mass spectrometry may be a powerful tool for screening potential electromagnetic-reaction protein markers. HSP70 and hnRNP K are involved in the stress reaction of HLECs exposed to microwaves. These cell responses are nonthermal effects of the electromagnetic field. Jpn J Ophthalmol 2007;51:412–416 © Japanese Ophthalmological Society 2007

The purpose of the study was to evaluate the outcome of the use of the temporary amniotic membrane patch (TAMP) for the treatment of primary pterygium and to investigate the mechanisms of reducing the recurrence rate.Twenty eyes in 20 patients with primary pterygium underwent pterygium excision followed by TAMP for 5 days. Removed amniotic membrane (AM) was immunostained with primary antibodies CD34, c-Kit, STRO-1 and AC133.Within the period of follow-up (53.3+/-13.8 months), all the eyes showed a smooth ocular surface without recurrence of pterygium. Different grades of CD34, c-Kit, STRO-1and AC133 positive stem and progenitor cells infiltrated or attached to the stroma of patched AM, with more spindle-shaped c-Kit cells than ovoid-shaped CD34 and AC133 cells.The temporary amniotic membrane patch is an effective and safe procedure for the treatment of primary pterygium. Absorbing excessive stem and progenitor cells may be one of the mechanisms of reducing the recurrence rate using AM.

Effects of exposure to 1.8 GHz radiofrequency field on the expression of Hsps and phosphorylation of MAPKs in human lens epithelial cells

To describe a Chinese patient with Marfan syndrome who had a unique phenotype and a recurrent mutation in the fibrillin-1 (FBN1) gene. A 31-year-old man who had a spontaneous bilateral lens dislocation into the vitreous cavity in childhood was found to have retinal and choroidal detachments in both eyes. A congenital atrial septal defect was detected. Pars plana vitrectomy, lensectomy, and silicone oil tamponade were performed on his right eye. Genomic DNA was extracted from leukocytes of peripheral blood, and the 65 exons and flanking intronic sequences of the FBN1 gene were amplified by polymerase chain reaction for mutational screening. A recurrent mutation, c.364C>T was detected in exon 4 that resulted in p.Arg122Cys. The visual acuity of the right eye improved to 6/60 one year after the surgeries. DNA screening helps in the diagnosis of Marfan syndrome with unique phenotypes. The mutation c.364C>T can be considered to be a hotspot for Marfan patients with predominant ectopia lentis.

Background A noninferiority trial was conducted to evaluate the efficacy of a single evening dose of fixed-combination latanoprost 50 μg/mL and timolol 0.5 mg/mL (Xalacom®; LTFC), in Chinese patients with primary open-angle glaucoma (POAG) or ocular hypertension (OH) who were insufficiently controlled on β-blocker monotherapy or β-blocker-based dual therapy. Methods This 8-week, randomized, open-label, parallel-group, noninferiority study compared once-daily evening dosing of LTFC with the unfixed combination of latanoprost, one drop in the evening, and timolol, one drop in the morning (LTuFC). The primary efficacy endpoint was the mean change from baseline to week 8 in diurnal intraocular pressure (IOP; mean of 8 AM, 10 AM, 2 PM, 4 PM IOPs). LTFC was considered noninferior to LTuFC if the upper limit of the 95% confidence interval (CI) of the difference was < 1.5 mmHg (analysis of covariance). Results Baseline characteristics were similar for LTFC (N = 125; POAG, 70%; mean IOP, 25.8 mmHg) and LTuFC (N = 125; POAG, 69%; mean IOP, 26.0 mmHg). Mean diurnal IOP changes from baseline to week 8 were -8.6 mmHg with LTFC and -8.9 mmHg with LTuFC (between-treatment difference: 0.3 mmHg; 95%-CI, -0.3 to 1.0). Both treatments were well tolerated. Conclusions A single evening dose of LTFC was at least as effective as the unfixed combination of latanoprost in the PM and timolol in the AM in reducing IOP in Chinese subjects with POAG or OH whose IOP was insufficiently reduced with β-blocker monotherapy or β-blocker-based dual therapy. LTFC is an effective and well tolerated once-daily treatment for POAG and OH. Trial registration Clinicaltrials.gov registration: NCT00219596

Reactive oxygen species (ROS) are chemically reactive molecules that perform essential functions in living organisms. Accumulating evidence suggests that many types of cancer cells exhibit elevated levels of ROS. Conversely, generation of ROS has become an effective method to kill cancer cells. (E)-3-hydroxy-3-(4-(4-nitrophenyl)-2-oxobut-3-en-1-yl) indolin-2-one, which is an NO2 group-containing compound designated herein as HOI-02, generated ROS and, in a dose-dependent manner, decreased esophageal cancer cell viability and inhibited anchorage-independent growth, followed by apoptosis and G2-M arrest. Moreover, results of an in vivo study using a patient-derived xenograft mouse model showed that HOI-02 treatment suppressed the growth of esophageal tumors, without affecting the body weight of mice. The expression of Ki-67 was significantly decreased with HOI-02 treatment. In addition, the phosphorylation of c-Jun, and expression of p21, cleaved caspase 3, and DCFH-DA were increased in the HOI-02-treated group compared with the untreated control group. In contrast, treatment of cells with (E)-3-(4-(4-aminophenyl)-2-oxobut-3-en-1-yl)-3-hydroxyindolin-2-one, which is an NH2 group-containing compound designated herein as HOI-11, had no effect. Overall, we identified HOI-02 as an effective NO2 group-containing compound that was an effective therapeutic or preventive agent against esophageal cancer cell growth.