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Objective Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disease in reproductive women, and the endocrine levels are also affected by diseases. The aim of this study was to determine the effect of thrombospondin-1 (TSP-1) on PCOS rat model. Methods We established the PCOS rat model, the serum hormones including TSP-1 expression were determined and morphological characteristics were investigated to evaluate the model. These above endocrine and morphological features were investigated again to evaluate the effect of TSP-1 treatment. Results In the PCOS model group, the serum hormones change (higher luteinizing hormone, testosterone and estrogen) and decreased TSP-1 expression levels were found compared with the control group. Besides, the morphological characteristics of PCOS were also observed in the model group. After TSP-1 treatment, the higher TSP-1, ANGPT2, PDGFB and PDGFD expression levels, the lower LH and T levels, decreased vessel density as well as VEGFA and ANGPT1 expression levels were found compared with the control group, and the ovary morphological changes were also observed in the TSP-1 experimental group. Conclusions TSP-1 delivery system might be an alternative therapy for PCOS treatment.

The homeostasis of the ocular lens is maintained by a microcirculation system propagated through gap junction channels. It is well established that the intercellular communications of the lens become deteriorative during aging. However, the molecular basis for this change in human lenses has not been well defined. Here, we present evidence to show that over 90% of Cx46 and Cx50 are lost in the fiber cells of normal human lenses aged 50 and above. From transparent to cataractous lenses, while Cx43 was upregulated, both Cx46 and Cx50 were significantly down-regulated in the lens epithelia. During aging of mouse lenses, Cx43 remained unchanged, but both Cx46 and Cx50 were significantly downregulated. Under oxidative stress treatment, mouse lenses develop in vitro cataractogenesis. Associated with this process, Cx43 was significantly upregulated, in contrast, Cx46 and Cx50 were sharply downregulated. Together, our results for the first time reveal that downregulation in Cx46 and Cx50 levels appears to be the major reason for the diminished coupling conductance, and the aging-dependent loss of Cx46 and Cx50 promotes senile cataractogenesis.

A novel coronavirus disease 2019 (COVID-19) was detected and has spread rapidly across various countries around the world since the end of the year 2019. Computed Tomography (CT) images have been used as a crucial alternative to the time-consuming RT-PCR test. However, pure manual segmentation of CT images faces a serious challenge with the increase of suspected cases, resulting in urgent requirements for accurate and automatic segmentation of COVID-19 infections. Unfortunately, since the imaging characteristics of the COVID-19 infection are diverse and similar to the backgrounds, existing medical image segmentation methods cannot achieve satisfactory performance. In this article, we try to establish a new deep convolutional neural network tailored for segmenting the chest CT images with COVID-19 infections. We first maintain a large and new chest CT image dataset consisting of 165,667 annotated chest CT images from 861 patients with confirmed COVID-19. Inspired by the observation that the boundary of the infected lung can be enhanced by adjusting the global intensity, in the proposed deep CNN, we introduce a feature variation block which adaptively adjusts the global properties of the features for segmenting COVID-19 infection. The proposed FV block can enhance the capability of feature representation effectively and adaptively for diverse cases. We fuse features at different scales by proposing Progressive Atrous Spatial Pyramid Pooling to handle the sophisticated infection areas with diverse appearance and shapes. The proposed method achieves state-of-the-art performance. Dice similarity coefficients are 0.987 and 0.726 for lung and COVID-19 segmentation, respectively. We conducted experiments on the data collected in China and Germany and show that the proposed deep CNN can produce impressive performance effectively. The proposed network enhances the segmentation ability of the COVID-19 infection, makes the connection with other techniques and contributes to the development of remedying COVID-19 infection.

Removing rain from images is of a great importance to various applications such as autonomous driving, drone piloting, and photo editing. Conventional methods rely on some heuristics to handcraft various priors to remove or separate rain from images. Recently, deep learning models are proposed to learn various end-to-end methods to complete this task. However, these methods might fail in obtaining satisfactory results in some real-world scenarios, especially when the captured images suffer from heavy rain that brings not only rain streaks but also a haze-like effect (caused by the accumulation of tiny raindrops). Different from most of the existing deep learning deraining methods that focus on handling rain streaks, we add a new variable to model the haze-like effect in a general model for rain, based on which a deep neural network is designed accordingly. Specifically, in our method, two branches are designed to handle rain streaks and the haze-like effect, respectively. The output of such branch structure is fed to an additional module to further enhance the performance. Three modules are trained jointly, leading to an end-to-end network, which supports a adjustment to the strength of removing the haze-like effect. Extensive experiments on several datasets show that our method outperforms several state-of-the-art methods in both objective assessment and visual quality.

The Chayu area is located at the southeastern margin of the Qinghai-Tibet Plateau. This region was considered to be in the southeastward extension of the Lhasa Block, bounded by Nujiang suture zone in the north and Yarlung Zangbo suture zone in the south. The Demala Group complex, a set of high-grade metamorphic gneisses widely distributed in the Chayu area, is known as the Precambrian metamorphic basement of the Lhasa Block in the area. According to field-based investigations and microstructure analysis, the Demala Group complex is considered to mainly consist of banded biotite plagiogneisses, biotite quartzofeldspathic gneiss, granitic gneiss, amphibolite, mica schist, and quartz schist, with many leucogranite veins. The zircon U-Pb ages of two granitic gneiss samples are 205 ± 1 Ma and 218 ± 1 Ma, respectively, representing the ages of their protoliths. The zircons from two biotite plagiogneisses samples show core-rim structures. The U-Pb ages of the cores are mainly 644 –446 Ma, 1213 –865 Ma, and 1780 –1400 Ma, reflecting the age characteristics of clastic zircons during sedimentation of the original rocks. The U-Pb ages of the rims are from 203 ± 2 Ma to 190 ± 1 Ma, which represent the age of metamorphism. The zircon U-Pb ages of one sample taken from the leucogranite veins that cut through granitic gneiss foliation range from 24 Ma to 22 Ma, interpreted as the age of the anatexis in the Demala Group complex. Biotite and muscovite separates were selected from the granitic gneiss, banded gneiss, and leucogranite veins for 40Ar/39Ar dating. The plateau ages of three muscovite samples are 16.56 ± 0.21 Ma, 16.90 ± 0.21 Ma, and 23.40 ± 0.31 Ma, and the plateau ages of four biotite samples are 16.70 ± 0.24 Ma, 16.14 ± 0.19 Ma, 15.88 ± 0.20 Ma, and 14.39 ± 0.20 Ma. The mica Ar-Ar ages can reveal the exhumation and cooling history of the Demala Group complex. Combined with the previous research results of the Demala Group complex, the authors refer that the Demala Group complex should be a set of metamorphic complex. The complex includes not only Precambrian basement metamorphic rock series, but also Paleozoic sedimentary rock and Mesozoic granitic rock. Based on the deformation characteristics, the authors concluded that two stages of the metamorphism and deformation can be revealed in the Demala Group complex since the Mesozoic, namely Late Triassic-Early Jurassic (203 –190 Ma) and Oligocene –Miocene (24 –14 Ma). The early stage of metamorphism (ranging from 203 –190 Ma) was related to the Late Triassic tectono-magmatism in the area. The anatexis and uplifting-exhumation of the later stage (24 –14 Ma) were related to the shearing of the Jiali strike-slip fault zone. The Miocene structures are response to the large-scale southeastward escape of crustal materials and block rotation in Southeast Tibet after India-Eurasia collision. ©2021 China Geology Editorial Office.

Gonorrhea is one of the main sexually transmitted diseases in China. It mainly affects the genitourinary tract, and its clinical manifestations vary from asymptomatic to complicated types. The diagnosis of gonorrhea should be based on the patient's epidemiological history, clinical manifestations, and laboratory examination results. Treatment should be prompt and standardized and should involve the recommended treatment regimens. Patients should be appropriately followed up after treatment. The antimicrobial resistance of gonococcal isolates has become a severe problem of clinical concern. In order to provide technical guidance of the diagnosis and treatment of gonorrhea for health care workers, the authors developed the guidelines based on the version of 2014, which will be of important in the standardizing medical care of gonorrhea, and further facilitating control and prevention of the disease.

Based on the atom-bond electronegativity equalization method fused into molecular mechanics (ABEEM/MM), two fluctuating charge models of OH--water system were proposed. The difference between these two models is whether there is charge transfer between OH- and its first-shell water molecules. The structures, charge distributions, charge transfer, and binding energies of the OH-(H2O)n (n = 1-8, 10, 15, 23) clusters were studied by these two ABEEM/MM models, the OPLS/AA force field, the OPLS-SMOOTH/AA force field, and the QM methods. The results demonstrate that two ABEEM/MM models can search out all stable structures just as the QM methods, and the structures and charge distributions agree well with those from the QM calculations. The structures, the charge transfer, and the strength of hydrogen bonds in the first hydration shell are closely related to the coordination number of OH-. Molecular dynamics simulations on the aqueous OH- solution are performed at 298 and 278 K using ABEEM/MM-I model. The MD results show that the populations of three-, four-, and five-coordinated OH- are 29.6%, 67.1%, and 3.4% at 298 K, respectively, and those of two-, three-, four-, and five-coordinated OH- are 10.8%, 44.9%, 39.2%, and 4.9% at 278 K, respectively; the average hydrogen bond lengths and the hydrogen bond angle in the first shell increase with the temperature decreasing.

The general transcription factor, CREB has been shown to play an essential role in promoting cell proliferation, neuronal survival and synaptic plasticity in the nervous system. However, its function in stress response remains to be elusive. In the present study, we demonstrated that CREB plays a major role in mediating stress response. In both rat lens organ culture and mouse lens epithelial cells (MLECs), CREB promotes oxidative stress-induced apoptosis. To confirm that CREB is a major player mediating the above stress response, we established stable lines of MLECs stably expressing CREB and found that they are also very sensitive to oxidative stress-induced apoptosis. To define the underlying mechanism, RNAseq analysis was conducted. It was found that CREB significantly suppressed expression of the αB-crystallin gene to sensitize CREB-expressing cells undergoing oxidative stress-induced apoptosis. CREB knockdown via CRISPR/CAS9 technology led to upregulation of αB-crystallin and enhanced resistance against oxidative stress-induced apoptosis. Moreover, overexpression of exogenous human αB-crystallin can restore the resistance against oxidative stress-induced apoptosis. Finally, we provided first evidence that CREB directly regulates αB-crystallin gene. Together, our results demonstrate that CREB is an important transcription factor mediating stress response, and it promotes oxidative stress-induced apoptosis by suppressing αB-crystallin expression.

Controlling proliferation and aflatoxin production by Aspergillus flavus is a pressing challenge for global food safety and security. Marine bacterium Staphylococcus saprophyticus strain L-38 showed excellent antifungal activity toward A. flavus in vitro and in vivo. In sealed, non-contact confrontation assays, L-38 completely inhibited conidial germination and mycelial growth of A. flavus through the production of volatile organic compounds (VOCs). Gas chromatography-mass spectrometry identified 3,3-dimethyl-1,2-epoxybutane (3-DE) as the most abundant VOC (32.61% of total peak area, 78% matching). Exposure of A. flavus cultures to synthetic 3-DE similarly demonstrated strong inhibition of growth. Moreover, culture of L-38 in a sealed chamber with maize or peanuts artificially inoculated with A. flavus, at high water activity, resulted in significant inhibition of A. flavus germination and aflatoxin biosynthesis. Scanning electron microscopy of these samples revealed severe damage to conidial cells and hyphae compared to samples not exposed to L-38. L-38 also showed broad and effective antifungal activity toward eight other phytopathogenic fungi including Aspergillus niger, Fusarium verticillioides, Fusarium graminearum, Sclerotinia sclerotiorum, Rhizoctonia solani, Alternaria alternata, Monilinia fructicola, and Botrytis cinerea. This work introduces S. saprophyticus L-38 as a potential biocontrol agent and demonstrates the efficacy of the volatile 3-DE in the control of A. flavus and other destructive plant pathogens for post-harvest food safety.

Fungal secreted proteins that contain the Common in Fungal Extracellular Membrane (CFEM) domain are important for pathogenicity. The hemibiotrophic fungus Colletotrichum graminicola causes the serious anthracnose disease of maize. In this study, we identified 24 CgCFEM proteins in the genome of C. graminicola. Phylogenic analysis revealed that these 24 proteins (CgCFEM1—24) can be divided into 2 clades based on the presence of the trans-membrane domain. Sequence alignment analysis indicated that the amino acids of the CFEM domain are highly conserved and contain 8 spaced cysteines, with the exception that CgCFEM1 and CgCFEM24 lack 1 and 2 cysteines, respectively. Ten CgCFEM proteins with a signal peptide and without the trans-membrane domain were considered as candidate effectors and, thus were selected for structural prediction and functional analyses. The CFEM domain in the candidate effectors can form a helical-basket structure homologous to the Csa2 protein in Candida albicans, which is responsible for haem acquisition and pathogenicity. Subcellular localization analysis revealed that these effectors accumulate in the cell membrane, nucleus, and cytosolic bodies. Additionally, 5 effectors, CgCFEM6, 7, 8, 9 and 15, can suppress the BAX-induced programmed cell death in Nicotiana benthamiana with or without the signal peptide. These results demonstrate that these 10 CgCFEM candidate effectors with different structures and subcellular localizations in host cells may play important roles during the pathogenic processes on maize plants.

Endoscopic submucosal dissection (ESD) has been widely used in the treatment of early gastric cancer (EGC). A personalized and effective prediction method for ESD with EGC is urgently needed.To construct a risk prediction model for ulcers after ESD for EGC based on LASSO regression.A total of 196 patients with EGC who received ESD treatment were prospectively selected as the research subjects and followed up for one month. They were divided into an ulcer group and a non-ulcer group according to whether ulcers occurred. The general data, pathology, and endoscopic characteristics of the groups were compared, and the best risk predictor subsets were screened by LASSO regression and tenfold cross-validation. Multivariate logistic regression was applied to analyze the risk factors for ulcers after ESD in patients with EGC. A receiver operating characteristic (ROC) curve was used to estimate the predictive model performance.One month after the operation, no patient was lost to follow-up. The incidence of ulcers was 20.41% (40/196) (ulcer group), and the incidence of no ulcers was 79.59% (156/196) (non-ulcer group). There were statistically significant differences in the course of disease,Clopidogrel medication history, lesion diameter, convergent folds, and mucosal discoloration can predict the occurrence of ulcers after ESD in patients with EGC.

Corynebacterium glutamicum has been widely used for bulk and fine chemicals fermentation these years. In this study, we developed a defined medium for this bacteria based on the widely used CGXII minimal medium. We evaluated the effects of different components in CGXII on cell growth of C. glutamicum ATCC 13032 and improved the medium through single-factor experiment and central composite design (CCD). Urea, K(2)HPO(4) and MgSO(4) were found to be significant factors. 7 out of the total 15 components were modified. (NH(4))(2)SO(4), KH(2)PO(4), and protocatechuic acid were eliminated. Amounts of urea and MgSO(4) were increased, and concentrations of biotin and glucose were reduced. The resulting R2 medium was proved to be more suitable for cell growth, plasmid amplification and protein production than the original recipe. Remarkably, cell biomass accumulation in R2 increased by 54.36% than CGXII. Transcriptome analysis revealed alteration of carbon metabolism, cation transport and energy synthesis, which might be beneficial for cell growth in R2. Considering the high nitrogen content and availability of urea, the new medium is simplified and cost effective, which holds attractive potential for future study. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-02959-6.

The function of the transcription factor, cAMP response element‐binding protein (CREB), is activated through S133 phosphorylation by PKA and others. Regarding its inactivation, it is not well defined. cAMP response element‐binding protein plays an essential role in promoting cell proliferation, neuronal survival and the synaptic plasticity associated with long‐term memory. Our recent studies have shown that CREB is an important player in mediating stress response. Here, we have demonstrated that CREB regulates aging process through suppression of αB‐crystallin and activation of the p300‐p53‐Bak/Bax signaling axis. First, we determined that two specific protein phosphatases, PP‐1β and PP‐2Aα, can inactivate CREB through S133 dephosphorylation. Subsequently, we demonstrated that cells expressing the S133A‐CREB, a mutant mimicking constant dephosphorylation at S133, suppress CREB functions in aging control and stress response. Mechanistically, S133A‐CREB not only significantly suppresses CREB control of αB‐crystallin gene, but also represses CREB‐mediated activation of p53 acetylation and downstream Bak/Bax genes. cAMP response element‐binding protein suppression of αB‐crystallin and its activation of p53 acetylation are major molecular events observed in human cataractous lenses of different age groups. Together, our results demonstrate that PP‐1β and PP‐2Aα modulate CREB functions in aging control and stress response through de‐regulation of αB‐crystallin gene and p300‐p53‐Bax/Bak signaling axis, which regulates human cataractogenesis in the aging lens., This figure illustrates that the PP‐1β and PP‐2Aα modulate CREB functions in aging control and stress response through suppression of alphaB‐crystallin and activation of the p300‐p53‐Bax/Bak signaling axis in normal and cataractous lenses.

Lithium-rich manganese oxide is a promising candidate for the next-generation cathode material of lithium-ion batteries because of its low cost and high specific capacity. Herein, a series of xLi2MnO3·(1 − x)LiMnO2 nanocomposites were designed via an ingenious one-step dynamic hydrothermal route. A high concentration of alkaline solution, intense hydrothermal conditions, and stirring were used to obtain nanoparticles with a large surface area and uniform dispersity. The experimental results demonstrate that 0.072Li2MnO3·0.928LiMnO2 nanoparticles exhibit a desirable electrochemical performance and deliver a high capacity of 196.4 mAh g−1 at 0.1 C. This capacity was maintained at 190.5 mAh g−1 with a retention rate of 97.0% by the 50th cycle, which demonstrates the excellent cycling stability. Furthermore, XRD characterization of the cycled electrode indicates that the Li2MnO3 phase of the composite is inert, even under a high potential (4.8 V), which is in contrast with most previous reports of lithium-rich materials. The inertness of Li2MnO3 is attributed to its high crystallinity and few structural defects, which make it difficult to activate. Hence, the final products demonstrate a favorable electrochemical performance with appropriate proportions of two phases in the composite, as high contents of inert Li2MnO3 lower the capacity, while a sufficient structural stability cannot be achieved with low contents. The findings indicate that controlling the composition through a dynamic hydrothermal route is an effective strategy for developing a Mn-based cathode material for lithium-ion batteries.

As the important component of the eastern Tethys tectonic region, the Jinsha River-Ailao Mountain suture zone is often considered to be an ophiolitic melange belt. However, the P-T-t path and chronological framework of the metamorphic evolution in the collisional orogenetic process of this zone are still poorly understood owing to the lack of metamorphism research of symbolic high-pressure rocks. During a regional geological survey on a scale of 1 : 50000 in Gonjo County, Tibet Autonomous Region involved in this paper, (retrograde) eclogites lenses of different scales were found in Jinsha River suture zone, eastern Tibet for the first time. The (retrograde) eclogites can be divided into garnet-albite-chlorite-actinolite schists and eclogites according to retrograde degrees. The mainly mineral components of eclogites include garnet (45%–50%), clinopyroxene (about 25%), and hornblende (5%–10%) primarily, and biotite, quartz, rutile, and muscovite secondarily. According to the data of electron probe micro analysis (EPMA), clinopyroxenes feature high content of Na2O (5.6%–6%) and corresponding jadeite (Jd) molecules of 37%–44%, and they fall within the omphacite region in Quad-Jd-Ae diagram. The temperature and pressure of the metamorphism at peak are P≈2.2–2.34 GPa and T≈622–688 °C respectively as measured with geobarometry Grt-Omp-Phe and geothermometer Grt-Omp. This will provide a new reference for the understanding of Paleo-Tethyan evolution. In this paper, two samples of eclogites were chosen for LA-ICP-MS zircon U-Pb dating and their 206Pb/238U ages obtained are 240 ± 3 Ma and 244 ± 1 Ma respectively. Furthermore, the zircons feature extremely low Th/U ratio (

Endogenous substance such as nucleotide as a drug carrier has been proposed as a novel drug delivery system. The nucleotide guanosine-5′-monophosphate (GMP) is used to transport an anticancer drug pemetrexed disodium heptahydrate (PMX) via specific base pairing. The endogenous nature of GMP helps to avoid biocompatibility issues that are generally accompanied with nanocarriers including cytotoxicity, immunogenicity and blood compatibility. Furthermore, the low-molecular weight of the GMP nucleotide carrier significantly boosts the drug loading capacity compared to traditional liposomes and high-molecular weight carriers. Hydrogen-bonding interaction between the carrier and drug realizes the controlled release of loaded drug, and also facilitates large scale manufacture since no additional chemical synthesis is required. More importantly, in vivo experiments reveal that the base-paired GMP:PMX nanovesicles improve the target specificity and pharmacokinetic properties of PMX, and exhibit remarkably enhanced anticancer abilities compared to standalone PMX without any carriers. We envision that this strategy could be extended to other endogenous substances and drugs bearing functional groups capable of specific interaction, and promote the construction of drug delivery systems with inherent biocompatibility, enhanced drug delivery efficacy, and a simplified preparation method.

Fumonisin B1 (FB1) contamination in cereals and cereal products remains an important aspect of food safety because of its wide distribution and the potential health hazard. However, only a few microorganisms have been reported to effectively degrade FB1. In this present study, a bacterial consortium SAAS79 with highly FB1-degrading activity was isolated from the spent mushroom compost. The combination of antibiotic-driven selection and 16S rDNA sequencing identified the Pseudomonas genus as the key FB1-degrading member. The microbial consortium could degrade more than 90% of 10 μg/mL FB1 after incubation for 24 h at pH of 5–7 and temperature of 28–35 °C. The enzymes from the intracellular space were proved to be responsible for FB1 degradation, which eliminated about 90% of 10 μg/mL FB1 in 3 h. Besides, liquid chromatography time-of-flight mass spectrometry (LC-TOF/MS) analysis identified two degradation products of FB1, and their toxicity on the monkey kidney cells (MARC-145) was significantly lower (p

Traditional image quality assessment (IQA) methods do not perform robustly due to the shallow hand-designed features. It has been demonstrated that deep neural network can learn more effective features than ever. In this paper, we describe a new deep neural network to predict the image quality accurately without relying on the reference image. To learn more effective feature representations for non-reference IQA, we propose a two-stream convolution network that includes two subcomponents for image and gradient image. The motivation for this design is using a two-stream scheme to capture different-level information of inputs and easing the difficulty of extracting features from one steam. The gradient stream focuses on extracting structure features in details, and the image stream pays more attention to the information in intensity. In addition, to consider the locally non-uniform distribution of distortion in images, we add a region-based fully convolutional layer for using the information around the center of the input image patch. The final score of the overall image is calculated by averaging of the patch scores. The proposed network performs in an end-to-end manner in both the training and testing phases. The experimental results on a series of benchmark datasets, e.g., LIVE, CISQ, IVC, TID2013, and Waterloo Exploration Database, show that the proposed algorithm outperforms the state-of-the-art methods, which verifies the effectiveness of our network architecture.

Objective: It has been well established that sumoylation acts as an important regulatory mechanism that controls many different cellular processes. We and others have shown that sumoylation plays an indispensable role during mouse eye development. Whether sumoylation is implicated in ocular pathogenesis remains to be further studied. In the present study, we have examined the expression patterns of the de-sumoylation enzymes (SENPs) in the in vitro cataract models induced by glucose oxidase and UVA irradiation. Methods: Four-week-old C57BL/6J mice were used in our experiments. Lenses were carefully dissected out from mouse eyes and cultured in M199 medium for 12 hours. Transparent lenses (without surgical damage) were selected for experimentation. The lenses were exposed to UVA for 60 min or treated with 20 mU/mL glucose oxidase (GO) to induce cataract formation. The mRNA levels were analyzed with qRT-PCR. The protein levels were determined with western blot analysis and quantitated with Image J. Results: GO treatment and UVA irradiation can induce cataract formation in lens cultured in vitro. GO treatment significantly down-regulated the mRNA levels for SENPs from 50% to 85%; on the other hand, expression of seven SENP proteins under GO treatment appeared in 3 situations: upregulation for SENP1, 2 and 6; downregulation for SENP 5 and 8; and unchanged for SENP3 and 7. UVA irradiation upregulates the mRNAs for all seven SENPs; In contrast to the mRNA levels for 7 SENPs, the expression levels for 6 SENPs (SENP1-3, 5-6 and 8) appeared down-regulated from 10% to 50%, and only SENP7 was slightly upregulated. Conclusion: Our results for the first time established the differentiation expression patterns of 7 de-sumoylation enzymes (SENPs) under treatment by GO or UVA, which provide preliminary data to link sumoylation to stress-induced cataractogenesis.

Previous studies have shown that ghrelin, a peptide produced in the stomach, attenuates acute lung injury (ALI) in various animal models, and that some of these effects are associated with inhibition of the nuclear factor κB signaling pathway. This study investigated whether ghrelin exerts beneficial effects on hemorrhagic shock (HS)-induced ALI by modulating nuclear factor κB inhibitor kinase/nuclear factor κB inhibitor/nuclear factor κB (IKK/IκBα/NF-κB) pathway activity. HS was induced in male SD rats by withdrawing blood to a mean arterial pressure (MAP) of 40 mm Hg for 1 h; rats then received ghrelin (10 nmol/kg) or vehicle intravenously and were resuscitated with the shed blood and an equal volume of Ringer lactate solution followed by observation for 2 h. After resuscitation, samples were collected and analyzed for lung histopathology, wet to dry weight ratio (W/D), bronchoalveolar lavage fluid (BALF) protein, neutrophil infiltration, plasma inflammatory cytokines (TNF-α and IL-6), and cytoplasmic phosphorylated IKKβ, IκBα, phosphorylated IκBα and nuclear NF-κB expression. Compared to those in the two sham groups, lung injury, W/D, BALF protein, neutrophil infiltration, plasma TNF-α and IL-6 levels, and IKK/IκBα/NF-κB pathway activation were significantly increased in HS rats. After ghrelin administration, all parameters analyzed were decreased compared to those without ghrelin in HS rats. Moreover, ghrelin alleviated the decreased MAP after resuscitation compared to that in HS rats. Exogenous ghrelin attenuates the inflammatory response and acute lung injury after HS. These beneficial effects appear to be mediated through inhibition of IKK/IκBα/NF-κB signaling.

Exploiting intrinsic structures in sparse signals underpins the recent progress in compressive sensing (CS). The key for exploiting such structures is to achieve two desirable properties: generality (\ie, the ability to fit a wide range of signals with diverse structures) and adaptability (\ie, being adaptive to a specific signal). Most existing approaches, however, often only achieve one of these two properties. In this study, we propose a novel adaptive Markov random field sparsity prior for CS, which not only is able to capture a broad range of sparsity structures, but also can adapt to each sparse signal through refining the parameters of the sparsity prior with respect to the compressed measurements. To maximize the adaptability, we also propose a new sparse signal estimation where the sparse signals, support, noise and signal parameter estimation are unified into a variational optimization problem, which can be effectively solved with an alternative minimization scheme. Extensive experiments on three real-world datasets demonstrate the effectiveness of the proposed method in recovery accuracy, noise tolerance, and runtime., Comment: 13 pages, submitted to IEEE Transactions on Image Processing

PURPOSE Accumulated evidence have well established that protein sumoylation plays multiple roles in various cellular processes. In the vertebrate eye, we and others have demonstrated that sumoylation displays indispensable roles in regulating eye development. Various ocular cell lines including human embryonic cell line (FHL124), the SV40-large T-transformed human lens epithelial cell line (HLE), the SV40-large T-transformed mouse lens epithelial cell line (αTN4-1), the rabbit lens epithelial cell line (N/N1003A) and the human retina pigment epithelial cell line (ARPE-19) have been extensively used for studying various cellular functions and disease processes including sumoylation functions, and mechanisms for cataract and age-related macular degeneration (AMD). However, the sumoylation enzyme systems have not been well established. METHODS FHL124, HLE, αTN4-1, N/N1003A and ARPE-19 were cultured in Dulbecco's modified eagle medium (DMEM) containing 10% FBS and 1% penicillin & streptomycin. The expression levels of seven SENP mRNAs were analyzed with qRT-PCR, and the expression levels of seven SENP proteins were detected with Western blot analysis. RESULTS Using both qRT-PCR and Western blot analysis, we have obtained the followings: 1). The 3 human ocular cell lines, FHL124, HLE and ARPE-19 express all types of SENP mRNA and proteins. 2). In mouse lens epithelial cell line αTN4-1, and rabbit lens epithelial cells line N/N1003A, however, only the mRNAs for SENP1, 2, 3, 6 and 7 are expressed. At the protein level, SENP8 was absent in both αTN4-1 and N/N1003A cells; 3). Each cell line has different dominant SENP enzymes. For FHL124, SENP3, 5, 7 and 8 proteins are relatively dominant. SENP3, 5 and 6 are the major de-sumoylation enzymes in HLE cells. Different from human lens epithelial cells, FHL124 and HLE, human retina pigment epithelial cells (ARPE-19) have SENP3, 7, and 8 as the dominant forms of de-sumoylation enzymes. For mouse lens epithelial cells, SENP1, 3 and 7 are the major de-sumoylation enzymes. On the other hand, the rabbit lens epithelial cells have SENP1, 2 and 7 as the major isoforms. CONCLUSION Our results for the first time defined the differential expression patterns of the seven types of de-sumoylation enzymes (SENPs) in 5 major ocular cell lines. These results help to establish the basis for the future study of sumoylation functions and the related mechanisms in vertebrate eye.

Protein sumoylation is one of the most important post-translational modifications regulating many biological processes (Flotho A & Melchior F. 2013. Ann Rev. Biochem. 82:357–85). Our previous studies have shown that sumoylation plays a fundamental role in regulating lens differentiation (Yan et al., 2010. PNAS, 107(49):21034-9.; Gong et al., 2014. PNAS. 111(15):5574–9). Whether sumoylation is implicated in lens pathogenesis remains elusive. Here, we present evidence to show that the protein inhibitor of activated STAT-1 (PIAS1), a E3 ligase for sumoylation, is implicated in regulating stress-induced lens pathogenesis. During oxidative stress-induced cataractogenesis, expression of PIAS1 is significantly altered at both mRNA and protein levels. Upregulation and overexpression of exogenous PIAS1 significantly enhances stress-induced apoptosis. In contrast, silence of PIAS1 with CRISPR/Cas9 technology attenuates stress-induced apoptosis. Mechanistically, different from other cells, PIAS1 has little effect to activate JNK but upregulates Bax, a major proapoptotic regulator. Moreover, Bax upregulation is derived from the enhanced transcription activity of the upstream transcription factor, p53. As revealed previously in other cells by different laboratories, our data also demonstrate that PIAS1 promotes SUMO1 conjugation of p53 at K386 residue in lens epithelial cells and thus enhances p53 transcription activity to promote Bax upregulation. Silence of Bax expression largely abrogates PIAS1-mediated enhancement of stress-induced apoptosis. Thus, our results demonstrated that PIAS1 promotes oxidative stress-induced apoptosis through positive control of p53, which specifically upregulates expression of the downstream proapoptotic regulator Bax. As a result, PIAS1-promoted apoptosis induced by oxidative stress is implicated in lens pathogenesis.

Background Osteoporosis seriously disturbs the life of people. Meanwhile, inhibition or weakening of osteogenic differentiation is one of the important factors in the pathogenesis of osteoporosis. It was reported that miR-27a-3p reduced the symptoms of osteoporosis. However, the mechanism by which miR-27a-3p in osteogenic differentiation remains largely unknown. Methods To induce the osteogenic differentiation in MC3T3-E1 cells, cells were treated with osteogenic induction medium (OIM). RT-qPCR was used to evaluate the mRNA expression of miR-27a-3p and CRY2 in cells. The protein levels of CRY2, Runt-related transcription factor 2 (Runx2), osteopontin (OPN), osteocalcin (OCN) and the phosphorylation level of extracellular regulated protein kinases (ERK) 1/2 in MC3T3-E1 cells were evaluated by western blotting. Meanwhile, calcium nodules and ALP activity were tested by alizarin red staining and ALP kit, respectively. Luciferase reporter gene assay was used to analyze the correlation between CRY2 and miR-27a-3p. Results The expression of miR-27a-3p and the phosphorylation level of ERK1/2 were increased by OIM in MC3T3-E1 cells, while CRY2 expression was decreased. In addition, OIM-induced increase of calcified nodules, ALP content and osteogenesis-related protein expression was significantly reversed by downregulation of miR-27a-3p and overexpression of CRY2. In addition, miR-27a-3p directly targeted CRY2 and negatively regulated CRY2. Meanwhile, the inhibitory effect of miR-27a-3p inhibitor on osteogenic differentiation was reversed by knockdown of CRY2 or using honokiol (ERK1/2 signal activator). Furthermore, miR-27a-3p significantly inhibited the apoptosis of MC3T3-E1 cells treated by OIM. Taken together, miR-27a-3p/CRY2/ERK axis plays an important role in osteoblast differentiation. Conclusions MiR-27a-3p promoted osteoblast differentiation via mediation of CRY2/ERK1/2 axis. Thereby, miR-27a-3p might serve as a new target for the treatment of osteoporosis.

Recently, a growing body of evidence has suggested that abnormal ovarian angiogenesis, secondary to the imbalance between various angiogenic markers, is involved in the pathogenesis of PCOS, and this has led to the use of various interventions (such as Diane-35) to restore the normal ovarian angiogenesis. Therefore, we conducted the current investigation to determine the role of such markers (endothelial growth factor (VEGF), endostatin (ES), and thrombospondin-1 (TSP-1)) in the pathogenesis of PCOS along with the associated changes in ovarian blood flow in patients with PCOS compared to healthy controls, both before and after a course of oral contraception. A total of 381 patients with PCOS and 98 healthy females of childbearing age were recruited from July 2014 to June 2017 at the Reproductive Center of the Second Affiliated Hospital of Harbin Medical University. The serum levels of VEGF, ES, and TSP-1 were determined by enzyme-linked immunosorbent assay, while ovarian perfusion was measured by the pulsatility index (PI) and resistance index (RI) by using transvaginal color Doppler ultrasound. Repeated analyses were carried out after 3 months of Diane-35 treatment. Post-treatment serum levels of luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratio of patients with PCOS decreased significantly (P

Myocardial infarction (MI) is a severe cardiovascular disease. Some M1 macrophage-derived extracellular vesicles (EVs) are involved in the inhibition of angiogenesis and acceleration dysfunction during MI. However, the potential mechanism of M1 phenotype bone marrow-derived macrophages- (BMMs-) EVs (M1-BMMs-EVs) in MI is largely unknown. This study sought to investigate whether M1-BMMs-EVs increased CDC42 expression and activated the MEK/ERK pathway by carrying lncRNA MALAT1 and competitively binding to miR-25-3p, thus inhibiting angiogenesis and myocardial regeneration after MI. After EV treatment, the cardiac function, infarct size, fibrosis, angiogenesis, and myocardial regeneration of MI mice and the viability, proliferation and angiogenesis of oxygen-glucose deprivation- (OGD-) treated myocardial microvascular endothelial cells (MMECs) were assessed. MALAT1 expression in MI mice, cells, and EVs was detected. MALAT1 downstream microRNAs (miRs), genes, and pathways were predicted and verified. MALAT1 and miR-25-3p were intervened to evaluate EV effects on OGD-treated cells. In MI mice, EV treatment aggravated MI and inhibited angiogenesis and myocardial regeneration. In OGD-treated cells, EV treatment suppressed cell viability, proliferation, and angiogenesis. MALAT1 was highly expressed in MI mice, OGD-treated MMECs, M1-BMMs, and EVs. Silencing MALAT1 weakened the inhibition of EV treatment on OGD-treated cells. MALAT1 sponged miR-25-3p to upregulate CDC42. miR-25-3p overexpression promoted OGD-treated cell viability, proliferation, and angiogenesis. The MEK/ERK pathway was activated after EV treatment. Collectively, M1-BMMs-EVs inhibited angiogenesis and myocardial regeneration following MI via the MALAT1/miR-25-3p/CDC42 axis and the MEK/ERK pathway activation.

Based on the atom-bond electronegativity equalization method fused into molecular mechanics (ABEEM/MM), two fluctuating charge models of OH

Purpose Protein Sumoylation is one of the most important and prevalent posttranscriptional modification. Increasing evidence have shown that the SENPs (sentrin/SUMOspecific proteases) are critical for steady-state levels of SUMO modification of target proteins, and protein de-sumoylation modulates a great diversity of biological processes including transcription, development, differentiation, neuroprotection, as well as pathogenesis. In the vertebrate eye, we and others have previously shown that sumoylation participated in the differentiation of major ocular tissues including retina and lens. However, the biological significance of seven SENP enzymes: SENP1 to 3 and SENP5 to 8 have not be fully investigated in the ocular tissues. Methods The 5 major ocular cell lines were cultured in Dulbecco's modified Eagle's medium (DMEM) containing fetal bovine serum (FBS) or rabbit serum (RBS) and 1% Penicillin- Streptomycin. The mRNA levels were analysed with qRT-PCR. The protein levels were determined with western blot analysis and quantitated with Image J. Results At the mRNA level, all SENPs were highly expressed in retina, and much reduced expression patterns in cornea, lens epithelium and lens fiber. At the protein level, SENP1 to -3, and SENP6 were highly abundant in cornea, while SENP5, SENP7 and SENP8 were enriched in retina, and these SENPs were relatively less abundant in lens tissues. Conclusion Our results for the first time established the differentiation expression patterns of the 7 de-sumoylation enzymes (SENPs), which provides a basis for further investigation of protein desumoylation functions in vertebrate eye.

Purpose It is now well established that protein sumoylation acts as an important regulatory mechanism modulating functions over three thousand proteins. In the vision system, protein conjugation with SUMO peptides can regulate differentiation of multiple ocular tissues. Such regulation is often explored through analysis of biochemical and physiological changes with various cell lines in vitro. We have recently analyzed the expression levels of both mRNAs and proteins for seven de-sumoylation enzymes (SENPs) in five major ocular cell lines. In continuing the previous study, here we have determined their cellular localization of the seven de-sumoylation enzymes (SENP1, 2, 3, 5, 6, 7 and 8) in the above 5 major ocular cell lines using immunocytochemistry. Methods The 5 major ocular cell lines were cultured in Dulbecco's modified Eagle's medium (DMEM) containing fetal bovine serum (FBS) or rabbit serum (RBS) and 1% Penicillin- Streptomycin. The localization of the 7 major de-sumoylation enzymes (SENPs) in the 5 major ocular cell lines were determined with immunohistochemistry. The images were captured with a Zeiss LSM 880 confocal microscope. Results 1) The SENP1 was localized in both cytoplasm and nucleus of 3 human ocular cell lines, FHL124, HLE and ARPE-19; In N/N1003A and αTN4-1, SENP 1 was more concentrated in the cytoplasm. SENP1 appears in patches; 2) SENP2 was distributed in both cytoplasm and nucleus of all ocular cell lines in patches. In HLE and ARPE-19 cells, SENP2 level was higher in nucleus than in cytoplasm; 3) SENP3 was almost exclusively concentrated in the nuclei in all ocular cells except for N/N1003A cells. In the later cells, a substantial amount of SENP3 was also detected in the cytoplasm although nuclear SENP3 level was higher than the cytoplasmic SENP3 level. SENP3 appeared in obvious patches in the nuclei; 4) SENP5 was dominantly localized in the cytoplasm (cellular organelles) near nuclear membrane or cytoplasmic membrane ; 5) SENP6 was largely concentrated in the nuclei of all cell lines except for αTN4-1 cells. In the later cells, a substantial amount of SENP6 was also detected in the cytoplasm although nuclear SENP6 level was higher than the cytoplasmic SENP6 level. 6) SENP7 has an opposite localization pattern between human and animal cell lines. In human cell lines, a majority of SENP7 was localized in nuclei whereas in mouse and rabbit lens epithelial cells, most SENP7 was distributed in the cytoplasm. SENP8 was found present in human cell lines. The 3 human ocular cell lines had relatively similar distribution pattern. In FHL124 and ARPE-19 cells, SENP8 was detected only in the cytoplasm, but in HLE cells, patches of SENP8 in small amount was also detected in the nuclei. Conclusions Our results for the first time defined the differential distribution patterns of seven desumoylation enzymes (SENPs) in 5 major ocular cell lines. These results help to understand the different functions of various SENPs in maintaining the homeostasis of protein sumoylation patterns during their functioning processes.

Background It is now well established that protein sumoylation is an important mechanism to regulate multiple cellular processes including gene transcription, chromatin structure, cell proliferation and differentiation, as well as pathogenesis. Objective In the vertebrate eye, we and others have previously shown that sumoylation can regulate differentiation of major ocular tissues including retina and lens. However, the expression patterns of the three types of sumoylation enzymes, the activating enzymes SAE1 and UBA2, the conjugating enzyme UBC9, and the ligating enzymes such as RanBP2 and PIAS1 have not been well studied in the ocular tissues. Conclusion In the present study, using QRT-PCR and western blot analysis, we have determined the differentiatial expression patterns of the above three types of enzymes, and the obtained results lay down a foundation for further exploration of sumoylation functions in vertebrate eye.

As an integral component of blind image deblurring, non-blind deconvolution removes image blur with a given blur kernel, which is essential but difficult due to the ill-posed nature of the inverse problem. The predominant approach is based on optimization subject to regularization functions that are either manually designed, or learned from examples. Existing learning based methods have shown superior restoration quality but are not practical enough due to their restricted and static model design. They solely focus on learning a prior and require to know the noise level for deconvolution. We address the gap between the optimization-based and learning-based approaches by learning a universal gradient descent optimizer. We propose a Recurrent Gradient Descent Network (RGDN) by systematically incorporating deep neural networks into a fully parameterized gradient descent scheme. A hyper-parameter-free update unit shared across steps is used to generate updates from the current estimates, based on a convolutional neural network. By training on diverse examples, the Recurrent Gradient Descent Network learns an implicit image prior and a universal update rule through recursive supervision. The learned optimizer can be repeatedly used to improve the quality of diverse degenerated observations. The proposed method possesses strong interpretability and high generalization. Extensive experiments on synthetic benchmarks and challenging real-world images demonstrate that the proposed deep optimization method is effective and robust to produce favorable results as well as practical for real-world image deblurring applications.

Sumoylation is one of the key regulatory mechanisms in eukaryotes. Our previous studies reveal that sumoylation plays indispensable roles during lens differentiation (Yan et al. 2010. Proc Natl Acad Sci USA. 107:21034–21039; Gong et al. 2014. Proc Natl Acad Sci USA. 111:5574–5579). Whether sumoylation is implicated in cataractogenesis, a disease largely derived from aging, remains elusive. In the present study, we have examined the changing patterns of the sumoylation ligases and de‐sumoylation enzymes (SENPs) and their substrates including Pax6 and other proteins in cataractous lenses of different age groups from 50 to 90 years old. It is found that compared with normal lenses, sumoylation ligases 1 and 3, de‐sumoylation enzymes SENP3/7/8, and p46 Pax6 are clearly increased. In contrast, Ubc9 is significantly decreased. Among different cataract patients from 50s to 70s, male patients express more sumoylation enzymes and p46 Pax6. Ubc9 and SENP6 display age‐dependent increase. The p46 Pax6 displays age‐dependent decrease in normal lens, remains relatively stable in senile cataracts but becomes di‐sumoylated in complicated cataracts. In contrast, sumoylation of p32 Pax6 is observed in senile cataracts and increases its stability. Treatment of rat lenses with oxidative stress increases Pax6 expression without sumoylation but promotes apoptosis. Thus, our results show that the changing patterns in Ubc9, SENP6, and Pax6 levels can act as molecular markers for senile cataract and the di‐sumoylated p46 Pax6 for complicated cataract. Together, our results reveal the presence of molecular signature for both senile and complicated cataracts. Moreover, our study indicates that sumoylation is implicated in control of aging and cataractogenesis., The molecular signatures for both senile cataract and complicated cataract. Upregulation of sumoylation ligases Ubc9 and PIAS1, and de‐sumoylation enzyme SENP6, and SUMO1 conjugation of p32 Pax6 are molecular markers for senile cataract. Di‐sumoylation of p46 Pax6 is the molecular marker for complicated cataract.

According to the fact that 5-nitro-3-trinitromethyl-1H-1,2,4 triazole (NTNMT) is a successful, good explosive, energetic groups such as -CH

The widespread existence of potentially toxic heavy elements have become one of the serious environmental concerns around the globe. Thus, it is highly important to develop efficient and selective chemical sensors to detect such potentially toxic elements. Herein, we developed a rhodamine-2-amino-5-bromopyrimidine based chemosensor (RBP) for the selective detection of toxic elements using Hg2+ and Cr3+ as model elements in combination with other competitive ions such as Al3+, Ag+, Ca2+, Ba2+, Cd2+, Fe2+, Fe3+, Li+, K+, Mn2+, Mg2+, Cu2+, Na+, Ni2+, Pb2+and Zn2+. The newly developed RBP displayed good visibility, high sensitivity, excellent selectivity, high binding ability and low limit of detection in CH3CN/HEPES buffer (1 mM 3:2 v/v, pH 7.3) as a medium. The binding constants of RBP for Hg2+ and Cr3+ were 1.09 × 107 M−1 and 8.3 × 104 M−1, respectively. As compared to earlier reported studies, the lowest detection limits (LOD), i.e., 1.6 μM for Hg2+ and 4.9 μM for Cr3+ were recorded. RBP also show reversible binding affinity with Hg2+ and Cr3+ in the presence of ethylenediaminetetraacetate (EDTA). The binding mode between metal ions and RBP were further investigated by using density functional theory (DFT) calculations, which support the experimental findings very well. More importantly, RBP can be prepared as a test paper kit to detect the concentration of Hg2+ and Cr3+ ions by changing the color of the paper visible to naked eyes and is potential for the practical infield application. In addition, the results obtained from confocal microscopy revealed that the probe is cell permeable with low cytotoxicity and can be employed as a bio-imaging reagent for intracellular recognition of Hg2+ and Cr3+ ratification in human breast cancer cells MCF-7.

Tetra-amido macrocyclic ligand (TAML) activator is a functional analog of peroxidase enzymes, which activates hydrogen peroxide (H2O2) to form high valence iron-oxo complexes that selectively degrade persistent aromatic organic contaminants (ACs) in water. Here, we develop quantitative structure–activity relationship (QSAR) models based on measured pseudo first-order kinetic rate coefficients ( k obs ) of 29 ACs (e.g., phenols and pharmaceuticals) oxidized by TAML/H2O2 at neutral and basic pH values to gain mechanistic insight on the selectivity and pH dependence of TAML/H2O2 systems. These QSAR models infer that electron donating ability ( E HOMO ) is the most important AC characteristic for TAML/H2O2 oxidation, pointing to a rate-limiting single-electron transfer (SET) mechanism. Oxidation rates at pH 7 also depend on AC reactive indices such as f m i n − and qH+, which respectively represent propensity for electrophilic attack and the most positive net atomic charge on hydrogen atoms. At pH 10, TAML/H2O2 is more reactive towards ACs with a lower hydrogen to carbon atoms ratio (#H:C), suggesting the significance of hydrogen atom abstraction. In addition, ln k obs of 14 monosubstituted phenols is negatively correlated with Hammett constants (σ) and exhibits similar sensitivity to substituent effects as horseradish peroxidase. Although accurately predicting degradation rates of specific ACs in complex wastewater matrices could be difficult, these QSAR models are statistically robust and help predict both relative degradability and reaction mechanism for TAML/H2O2-based treatment processes.

Herein, we report a new rhodamine-based multianalyte (Cu2+ and Hg2+) fluorescent sensor RH-FP. The synthesized probe acts as a dual chemosensor for recognition of Cu2+ and Hg2+ in acetonitrile-water (4:1 v/v, pH 7.2 with 10 mM, HEPES) in the presence of other miscellaneous metal cations i.e. Ag+, Al3+, Ba2+, Ca2+, Cd2+, Fe3+, Fe2+, K+, Li+, Mg2+, Mn2+, Cu+2, Pb2+, Ni2+, Na+ and Zn2+. A highly selective and sensitive colorimetric (colorless to pink) response accompanied by a significant increase in absorption and emission maxima (250-folds) was observed by the interaction of RH-FP and Cu2+ or Hg2+. This makes RH-FP a suitable “bare-eye” detector. The Job’s plot and ESI–MS confirm 1:1 binding stoichiometry between sensor RH-FP and metal cations. The calculated binding constant for the complexes (RH-FP-Cu2+ and RH-FP-Hg2+) are 3.37 × 105 mol−1 and 7.6 × 105 mol−1, with a detection limit of 3.9 nm and 2.36 nm respectively. The binding mechanism was confirmed by Fourier transform infra-red spectroscopy (FT-IR) 1H, 13C NMR and density functional theory (DFT) calculations. Moreover, the fluorescent sensor RH-FP displayed potential in-field applications as detection kit and in fluorescent imaging of biological systems to detect Cu2+ or Hg2+.

Significance Oxidative stress-induced damage to retinal pigmented epithelial (RPE) cells is critically implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Here we report that oxidative stress-induced heterochromatin formation is essential to promote RPE survival. Mechanistically, oxidative damage-induced formation of heterochromatin occurs at the 53 target promoters of apoptosis genes and is regulated by p53 sumoylation. Our study demonstrates mechanistic links among chromatin conformation, p53 sumoylation, and RPE cell death. We propose that targeting heterochromatin provides a novel strategy for AMD treatment., Oxidative stress (OS)-induced retinal pigment epithelium (RPE) cell apoptosis is critically implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Heterochromatin, a compact and transcriptional inert chromatin structure, has been recently shown to be dynamically regulated in response to stress stimuli. The functional mechanism of heterochromatin on OS exposure is unclear, however. Here we show that OS increases heterochromatin formation both in vivo and in vitro, which is essential for protecting RPE cells from oxidative damage. Mechanistically, OS-induced heterochromatin selectively accumulates at p53-regulated proapoptotic target promoters and inhibits their transcription. Furthermore, OS-induced desumoylation of p53 promotes p53–heterochromatin interaction and regulates p53 promoter selection, resulting in the locus-specific recruitment of heterochromatin and transcription repression. Together, our findings demonstrate a protective function of OS-induced heterochromatin formation in which p53 desumoylation-guided promoter selection and subsequent heterochromatin recruitment play a critical role. We propose that targeting heterochromatin provides a plausible therapeutic strategy for the treatment of AMD.

We calculate the cross-correlation function $\langle (\Delta T/T)(\mathbf{v}\cdot \mathbf{n}/\sigma_{v}) \rangle$ between the kinetic Sunyaev-Zeldovich (kSZ) effect and the reconstructed peculiar velocity field using linear perturbation theory, to constrain the optical depth $\tau$ and peculiar velocity bias of central galaxies with Planck data. We vary the optical depth $\tau$ and the velocity bias function $b_{v}(k)=1+b(k/k_{0})^{n}$, and fit the model to the data, with and without varying the calibration parameter $y_{0}$ that controls the vertical shift of the correlation function. By constructing a likelihood function and constraining $\tau$, $b$ and $n$ parameters, we find that the quadratic power-law model of velocity bias $b_{v}(k)=1+b(k/k_{0})^{2}$ provides the best-fit to the data. The best-fit values are $\tau=(1.18 \pm 0.24) \times 10^{-4}$, $b=-0.84^{+0.16}_{-0.20}$ and $y_{0}=(12.39^{+3.65}_{-3.66})\times 10^{-9}$ ($68\%$ confidence level). The probability of $b>0$ is only $3.12 \times 10^{-8}$ for the parameter $b$, which clearly suggests a detection of scale-dependent velocity bias. The fitting results indicate that the large-scale ($k \leq 0.1\,h\,{\rm Mpc}^{-1}$) velocity bias is unity, while on small scales the bias tends to become negative. The value of $\tau$ is consistent with the stellar mass--halo mass and optical depth relation proposed in the previous literatures, and the negative velocity bias on small scales is consistent with the peak background-split theory. Our method provides a direct tool to study the gaseous and kinematic properties of galaxies., Comment: 13 pages, 13 figures, 3 tables