Search

At present, while the Internet of Things (IoT) devices bring convenience to people, security issues have led to an increasing number of threats to IoT security. Since IoT devices have a Web application system for device managers to operate, the system can view device information, control and configure device status, and its security is of great significance. Among the various authentication methods provided by IoT devices, the password information authentication mechanism is still a critical method for Web login. If the IoT device has a weak Web password, once a hacker discovers the device, it is straightforward to be attacked and implanted with malicious code to control the device and attack other devices in the network. In response to this problem, this paper designs a set of automatic detection frameworks for weak passwords for web application systems of IoT devices. Based on this framework, an automated weak password detection system was developed to detect weak Web passwords on IoT devices on the wide-area networks of Beijing, Shandong Province, and Zhejiang Province. A total of 12,179 devices with weak Web passwords were found, accounting for all discovered IoT devices of 7.58%, verifying the effectiveness of the proposed framework.

The signaling pathway of the gaseous hormone ethylene is involved in plant reproduction, growth, development, and stress responses. During reproduction, the two synergid cells of the angiosperm female gametophyte both undergo programmed cell death (PCD)/degeneration but in a different manner: PCD/degeneration of one synergid facilitates pollen tube rupture and thereby the release of sperm cells, while PCD/degeneration of the other synergid blocks supernumerary pollen tubes. Ethylene signaling was postulated to participate in some of the synergid cell functions, such as pollen tube attraction and the induction of PCD/degeneration. However, ethylene-mediated induction of synergid PCD/degeneration and the role of ethylene itself have not been firmly established. Here, we employed the CRISPR/Cas9 technology to knock out the five ethylene-biosynthesis 1-aminocyclopropane-1-carboxylic acid oxidase (ACO) genes and created Arabidopsis mutants free of ethylene production. The ethylene-free mutant plants showed normal triple responses when treated with ethylene rather than 1-aminocyclopropane-1-carboxylic acid, but had increased lateral root density and enlarged petal sizes, which are typical phenotypes of mutants defective in ethylene signaling. Using these ethylene-free plants, we further demonstrated that production of ethylene is not necessarily required to trigger PCD/degeneration of the two synergid cells, but certain components of ethylene signaling including transcription factors ETHYLENE-INSENSITIVE 3 (EIN3) and EIN3-LIKE 1 (EIL1) are necessary for the death of the persistent synergid cell.

Posterior capsular opacification (PCO) is the main postoperative complication after intraocular lens (IOL) implantation in cataract surgery, because of the proliferation of the residual lens epithelial cells (LECs) in the lens capsule. Drug-eluting IOLs, aimed to develop an in situ drug delivery device, are the promising concept in recent years. As IOLs are optical devices other than implants, the feasibility and applicability remain a challenge for drug-eluting coatings. In this investigation, a centrifugally concentric ring-patterned drug-loaded poly(lactide-co-glycolic acid) (PLGA) coating was designed and fabricated by the spin coating technique. The concentric ring-patterned morphologies and the drug loading and release properties were carefully investigated, and the spin coating parameters were optimized. A concentric annular coating with a thin center and thick periphery was obtained, which was particularly suitable for the surface modification of IOLs, as the visual pathway of the intraocular light transmission greatly requires good light transmittance of the IOLs. IOLs with the immunosuppressant cyclosporin A (CsA)-loaded coating (CsA @ PLGA) modification were then fabricated for PCO prevention. The in vitro LECs culture results showed that the CsA @ PLGA coating-modified IOLs significantly inhibited cell proliferation and induced cell death. Western blot analysis showed that the efficient cell inhibition behavior of CsA was due to the autophagy-mediated cell death pathway. The in vivo intraocular implantation results confirmed the desired PCO inhibition effect. Thus, the centrifugally concentric ring-patterned drug-loaded PLGA coating obtained by the spin coating technique provides a simple yet effective alternative of IOL modification for PCO prevention. Statement of Significance • Concentric ring-patterned polymer coating, specifically for drug-eluting IOL fabrication, was developed by the spin coating technique. • The immunosuppressant CsA inhibited LEC proliferation through the autophagy-mediated cell death pathway. • Concentric ring-patterned CsA-eluting IOLs exhibited reliable in vivo PCO prevention. • The drug-eluting IOLs fabricated by the simple and economical spin coating technique have a great potential in clinical translation.

COVID-19 quarantine provides the largest intervention data of myopia progression in schoolchildren. We found grade is an important risk factor, and COVID-19-induced modifications of student’s online time and outdoor activity time sufficiently change myopia progression.

Accurate communication at the stigma surface is required to promote plants' own pollen and reject foreign pollen. Liu et al. have now discovered an autocrine signaling pathway at the surface of arabidopsis stigmatic papillae, accumulating ROS. Downregulation of ROS production via an antagonistic peptide from the pollen coat promotes pollen hydration and germination.

Background and purpose: Complementary and Alternative Medicine(CAM) has been greatly used in cancer patients. This research aimed to explore the research priorities of CAM for cancer patient's treatment. Methods Web of Science(WoS), HistCite, BibExcel, GunnMap and VOSviewer were used to extract and visualize information. Results 2768 articles published in 789 journals were indexed in the WoS from 1989 to 2018. The USA(n = 1009) and Technion-Israel Institute Technology(n = 58) were the most prolific country and institution, respectively. Keywords co-occurrence analysis indicated that the research hotspots around the world formed five clusters, so did the author co-citation analysis. The research priorities of the top-five countries, the top-three prolific authors and the co-citation core authors were also discussed, which reveals the differences and similarities among them. Conclusion This study delineates a framework for better understanding the situational use of CAM in cancer patients, which could help health care workers to prioritize and organize future research.

RALFs are secreted peptides that are perceived by various CrRLK1L-LRE/LLG receptor complexes. The mechanistic basis of this perception has now been elucidated showing that the co-receptor LLG binds RALF23 to nucleate a FER receptor complex. This interaction likely occurs in other tissues where RALFs meet CrRLK1L receptors and LRE/LLG co-receptors.

Targeting microRNAs (miRNAs) with drug small molecules (SMs) is a new treatment method for many human complex diseases. Unsurprisingly, identification of potential miRNA-SM associations is helpful for pharmaceutical engineering and disease therapy in the field of medical research. In this paper, we developed a novel computational model of HeteSim-based inference for SM-miRNA Association prediction (HSSMMA) by implementing a path-based measurement method of HeteSim on a heterogeneous network combined with known miRNA-SM associations, integrated miRNA similarity, and integrated SM similarity. Through considering paths from an SM to a miRNA in the heterogeneous network, the model can capture the semantics information under each path and predict potential miRNA-SM associations based on all the considered paths. We performed global, miRNA-fixed local and SM-fixed local leave one out cross validation (LOOCV) as well as 5-fold cross validation based on the dataset of known miRNA-SM associations to evaluate the prediction performance of our approach. The results showed that HSSMMA gained the corresponding areas under the receiver operating characteristic (ROC) curve (AUCs) of 0.9913, 0.9902, 0.7989, and 0.9910 ± 0.0004 based on dataset 1 and AUCs of 0.7401, 0.8466, 0.6149, and 0.7451 ± 0.0054 based on dataset 2, respectively. In case studies, 2 of the top 10 and 13 of the top 50 predicted potential miRNA-SM associations were confirmed by published literature. We further implemented case studies to test whether HSSMMA was effective for new SMs without any known related miRNAs. The results from cross validation and case studies showed that HSSMMA could be a useful prediction tool for the identification of potential miRNA-SM associations. Keywords: microRNA, small molecule, association prediction, HeteSim algorithm, heterogeneous network

The association between near work activities and myopia has not been clearly established. This study establishes a model for near work myopia (NWM) induced by short viewing distance in guinea pigs with a carefully controlled visual environment, and evaluates the effect of viewing distance in myopia development. Pigmented guinea pigs (3 weeks old) were randomly assigned to 3 groups: near work (NW)-, form-deprivation (FD)-, and -4D hyperopic-defocus (HD)-induced myopia. Animals in NW groups were kept in cylindrical cages with vertical square-wave gratings, providing short- (S, d = 18 cm), middle- (M, d = 44 cm), and long- (L, d = 88 cm) mean viewing distances, all at the same illuminance, during daily treatment for 14 days. Biometric parameters, including refraction, anterior chamber depth (ACD), lens thickness (LT), vitreous chamber depth (VCD), and axial length (AL), were measured at the beginning and end of 14 days' treatment. Choroidal thickness (ChT) and choroidal blood perfusion (ChBP) were measured by optical coherence tomography (OCT) and OCT-angiography (OCTA), respectively, at the end of treatment. Refraction was shifted towards myopia in the S-cage group, compared with the M- and L-cage groups; refractions in the L-, M- and S-cage groups were 5.19 ± 0.65 D, 4.30 ± 0.64 D, and 0.53 ± 0.61 D, respectively (p 0.001). VCD and AL in the S-cage group increased in parallel with the myopic shift (L vs M vs S: VCD: 3.15 ± 0.02 mm vs 3.17 ± 0.02 mm vs 3.26 ± 0.02 mm, p 0.001; AL: 7.99 ± 0.03 mm vs 8.03 ± 0.03 mm vs 8.15 ± 0.02 mm, p = 0.001). In FD and HD eyes, changes similar to those in the S-cage group (near-work group, NW) were seen in refraction (NW vs FD vs HD: 5.36 ± 0.82 D vs -5.78 ± 0.44 D vs -4.96 ± 0.54 D, p = 0.734), ACD, LT, VCD and AL. Also, ChT and ChBP were significantly less in the S-cage group than in the M- and L-cage groups after 14 days' treatment (L vs M vs S: ChT: 74.84 ± 3.27 vs 76.07 ± 3.49 vs 61.95 ± 3.31, P = 0.002; ChBP: 48.32 ± 2.23 vs 48.66 ± 2.30 vs 38.14 ± 2.06, p = 0.002). Rearing in S-cages induced myopia in guinea pigs and correspondingly decreased ChBP and ChT. The present study provides objective evidence that short viewing distance could be a risk factor for myopia, and describes a useful model for studying the underlying mechanisms.

Purpose To construct a machine learning (ML)-based model for estimating the alignment curve (AC) curvature in orthokeratology lens fitting for vision shaping treatment (VST), which can minimize the number of lens trials, improving efficiency while maintaining accuracy, with regards to its improvement over a previous calculation method. Methods Data were retrospectively collected from the clinical case files of 1271 myopic subjects (1271 right eyes). The AC curvatures calculated with a previously published algorithm were used as the target data sets. Four kinds of machine learning algorithms were implemented in the experimental analyses to predict the targeted AC curvatures: robust linear regression models, support vector machine (SVM) regression models with linear kernel functions, bagging decision trees, and Gaussian processes. The previously published calculation method and the novel machine learning method were then compared to assess the final parameters of ordered lenses. Results The linear SVM and Gaussian process machine learning models achieved the best performance. The input variables included sex, age, horizontal visible iris diameter (HVID), spherical refraction (SER), cylindrical refraction, eccentricity value (e value), flat K (K1) and steep K (K2) readings, anterior chamber depth (ACD), and axial length (AL). The R-squared values for the output AC1K1, AC1K2 and AC2K1 values were 0.91, 0.84, and 0.73, respectively. The previous calculation method and machine learning methods displayed excellent consistency, and the proposed methods performed best based on flat K reading and e values. Conclusions The ML model can provide practitioners with an efficient method for estimating the AC curvatures of VST lenses and reducing the probability of cross-infection originating from trial lenses, which is especially useful during pandemics, such as that for COVID-19.

The process of eye axis lengthening in myopic eyes is regulated by multiple mechanisms in the retina, and horizontal cells (HCs) are an essential interneuron in the visual regulatory system. Wherein intracellular Ca

FnCpf1-mediated genome-editing technologies have enabled a broad range of research and medical applications. Recently, we reported that FnCpf1 possesses activity in human cells and recognizes a more compatible PAM (protospacer adjacent motif, 5'-KYTV-3'), compared with the other two commonly used Cpf1 enzymes (AsCpf1 and LbCpf1), which requires a 5'-TTTN-3' PAM. However, due to the efficiency and fidelity, FnCpf1-based clinical and basic applications remain a challenge. The direct repeat (DR) sequence is one of the key elements for FnCpf1-mediated genome editing. In principle, its engineering should influence the corresponding genome-editing activity and fidelity. Here we showed that the DR mutants [G(-9)A and U(-7)A] could modulate FnCpf1 performance in human cells, enabling enhancement of both genome-editing efficiency and fidelity. These newly identified features will facilitate the design and optimization of CRISPR-Cpf1-based genome-editing strategies.

Polymethacrylimide foam is fully closed-cell isotropic foam which possesses high stiffness and strength to weight ratios . The paper reports the findings of an experimental study developing to investigate the quasi-static and dynamic response of sandwich panels based on polymethacrylimide foam using compression tests and Split Hopkinson Pressure Bar , respectively. The effect of thickness of aluminum face sheet, thickness and density of the polymethacrylimide core on the mechanical properties of the sandwich structures are studied respectively. It is shown that core density has the greatest effect on compressive strength of sandwich structure. The elasticity modulus and compressive strength of sandwich decreased by 40% under quasi-static compressive when the density of the core reduced by 28%. Secondly, dynamic compressive experiment results show that when the density of the core reduced by 28%, at the strain rate of 150 s −1, compressive strength decreased by 45%; strain rate 310 s−1, compressive strength reduced by 42%. When the strain rate increased from 7.6 × 10−4 s−1 to 150 s−1 , compressive strength increased by 26%; strain rate increases from 7.6 × 10 −4 s−1 to 310 s−1, compressive strength increased by 43%. The dynamic mechanical properties of polymethacrylimide foam sandwich panels accompanied with the increase of strain rate. Finally, dynamic constitutive relation of Cowper-Symonds function is fitted.

Cardiovascular diseases (CVDs) are considered as the major reason for mortality and morbidity worldwide. Substantial evidence suggests that increased oxidative stress plays a significant role in the pathogenesis of CVDs, including atherosclerosis, hypertension, vascular endothelial dysfunction and ischemic heart disease. Cellular oxidative stress results in the release of toxic free radicals by endothelial cells and vascular smooth muscle cells that interact with cell components such as protein, DNA or lipid resulting in cardiovascular pathology. Silymarin has antioxidant activities against CVDs and offers protection against oxidative stress-induced hypertension, atherosclerosis and cardiac toxicity. We present a comprehensive review regarding the oxidative stress and protective effects of silymarin in CVDs management. We also aim to provide mechanistic insight of the mechanisms of silymarin action in oxidative stress-induced CVDs.

Two kinds of foam / fiber sandwich structures were prepared by using Vacuum Assisted Resin Transfer Molding (VARTM) process, on which the low-velocity impact tests were carried out. The force response, specific energy absorption and failure mode of the two sandwich structures under different impact energies, hammer shapes and impact positions were studied. From the force response and energy absorption curves, it can be seen that the corrugated sandwich structure outperformed the flat sandwich structure in terms of low-velocity impact resistance, and showed the best impact resistance when the impact was applied at the corrugated trough position. According to the observation of the impact profile of sandwich structure, the main failure modes of the sandwich structures include foam cracking, fiber breaking, fiber delamination, and debonding between fiber and foam.

Aiming at the problems of information storage security and information sharing among various medical information systems, combined with blockchain consensus mechanism, encryption mechanism, peer-to-peer network, and other technologies. A medical information system scheme based on blockchain is proposed to realize the storage and sharing of medical information. The program has the characteristics of non-tampering and decentralization. This paper has designed a Practical Byzantine fault tolerance (PBFT) medical blockchain information management system. This system is multi-node maintenance and shared management system that can prevent medical information data from being tampered with and medical information leakage. It can be used to solve Medical information data management problems. Compared with the existing medical blockchain system, this medical information management system has certain advantages and better applicability.

Retinal ischemia reperfusion (I/R) injury is common in many ophthalmic diseases. Recent studies have shown that toll-like receptor 4 (TLR4) is involved in ischemic retinal injury. Activation of TLRs requires specific accessory proteins such as myeloid differentiation protein 2 (MD2), which facilitate in ligand responsiveness. Therefore, inhibiting MD2 may be a novel approach to modulate TLR4 signaling and deleterious downstream effects in ischemic retinal injury. We used human Müller MIO-M1 cells treated with tert-butyl hydroperoxide (TBHP) to establish an in vitro I/R model of oxidative injury and tested the therapeutic effect of inhibiting MD2. Furthermore, we inhibited MD2 in a mouse model of retinal I/R injury and confirmed the results using MD2 knockout mice. Our studies show that pharmacological inhibition of MD2 prevented TBHP-induced reactive oxygen species (ROS) generation, inflammation and subsequent apoptosis in Müller cells. We also show that retinal I/R injury in mice induced functional deficits, increased ROS levels, inflammation and apoptosis. These pathological changes were not observed in MD2 knockout mice and attenuated when MD2 was inhibited in wildtype mice. In addition, we discovered that the mechanism of these therapeutic effects involved regulation of NADPH oxidase 4 (NOX4)-MD2-TLR4 complex formation. This study provides evidence that MD2 plays a key role in the pathogenesis of retinal I/R damage by participating in TLR4-NOX4 complex formation and elaboration of oxidative and inflammatory damage. Hence, inhibition of MD2 may reduce TLR-dependent damage during retinal I/R injury.

Male germline development in flowering plants involves two distinct and successive phases, microsporogenesis and microgametogenesis, which involve one meiosis followed by two rounds of mitosis. Many aspects of distinctions after mitosis between the vegetative cell and the male germ cells are seen, from morphology to structure, and the differential functions of the two cell types in the male gametophyte are differentially needed and required for double fertilization. The two sperm cells, carriers of the hereditary substances, depend on the vegetative cell/pollen tube to be delivered to the female gametophyte for double fertilization. Thus, the intercellular communication and coordinated activity within the male gametophyte probably represent the most subtle regulation in flowering plants to guarantee the success of reproduction. This review will focus on what we have known about the differentiation process and the functional diversification of the vegetative cell and the male germ cell, the most crucial cell types for plant fertility and crop production.

Bacteria can easily adhere on the surface of implants and subsequently form biofilm which lead to serious critical issues in the application. In the current work, poly(acrylic acid) (PAA) was firstly modified with dopamine (dopa) into dopa-PAA and was self-assembled with poly(ethylenimine)-AgNO 3 (PEI-AgNO 3 ) into multilayer films via layer-by-layer self-assembly technique. AgNO 3 were in situ reduced into silver nano particles (Ag NPs) in the process of multilayer film self-assembling using bio-inspired dopa as reducing agent. The morphology of the Ag NPs was characterized using transmission electron microscopy. In vitro , the (dopa-PAA/PEI-Ag NPs) n multilayer films showed a long-term sustained release of Ag + in PBS buffer. Zone of inhibition assays and the bacterial LIVE/DEAD staining methods demonstrated the high efficient and long-term bactericidal properties of the multilayer films. For the in vivo subcutaneous antibacterial tests in New Zealand white rabbits, the wound appearance and the histopathology analysis showed that implantation of the antibacterial coating modified PDMS promoted wound healing and showed good anti-inflammatory effect. The multilayer films also proved to be low cytotoxicity towards human lens epithelial cells, which can potentially be widely used to modify biomedical implants.

Background The control of cell proliferation is a fundamental aspect of tissue formation in development and regeneration. A cell type that illustrates this point particularly well is the neural crest-derived melanocyte, the pigment cell of vertebrates, as melanocytes can be followed easily during development and their pigment is directly visible in the integument of the adult. In mammals, melanocytes undergo physiological cycles of loss and proliferative regeneration during the hair cycle, and their proliferation is also critical during wound healing, repigmentation of depigmented lesions, and in melanoma formation and progression. Hence, a thorough analysis of the molecular parameters controlling melanocyte proliferation is crucial for our understanding of the physiology of this cell type both in health and disease. Objective SOX10 is a critical regulator in melanocytes and melanoma cells, but its specific role in their proliferation is far from clear. In this study we analyze the role of SOX10 in regulating mammalian melanocyte proliferation in a mouse model. Methods The role of SOX10 in melanoblast proliferation was analyzed in Sox10/+ mice by co-staining for melanocyte-specific markers and cell proliferation. In vitro, the role of SOX10 was studied by manipulating its levels using RNAi and analyzing the effects on DNA synthesis and cell growth and on gene expression at the RNA and protein levels. Results Reduction of Sox10 gene dose led to a reduction in the number of melanoblasts. Knockdown of Sox10 in melanocytes led to inhibition of cell proliferation and a decrease in the expression of the minichromosome maintenance complex component 5 (MCM5). In fact, SOX10 directly activated MCM5 transcription by binding to conserved SOX10 consensus DNA sequences in the MCM5 promoter. Furthermore, the defect in cell proliferation could be rescued partially by overexpression of MCM5 in Sox10 knockdown melanocytes. Conclusion The results suggest that the SOX10-MCM5 axis plays an important role in controlling melanocyte proliferation. Our findings provide novel insights into the regulatory mechanisms of melanocyte proliferation and may have implications for our understanding of the roles of SOX10 and MCM5 in abnormal melanocyte proliferation disorders such as cutaneous melanoma.

Corneal infection is an important cause of corneal damage and vision loss. In this work, aminoglycoside antibiotics were grafted onto polymer brushes modified contact lens through dynamic chemical bonds between polyphenol hydroxyls and phenylboronic acid. Both in vitro and in vivo antibacterial tests demonstrated the great promise in prevention of bacterial keratitis which could be attributed to the enhanced the retention time and drug bioavailability.

The dynamic fracture toughness of ice involves its fracture resistance under impact loading, which is essential for impact or blasting parameter selection and evaluation. Temperature is an important factor influencing ice mechanical properties. To examine the evolution of ice fracture characteristics at different loading rates and temperatures, notched semi-circular bend method was applied to determine the freshwater ice quasi-static and dynamic fracture toughness. A modified low-temperature split Hopkinson pressure bar system was developed to measure dynamic ice fracturing properties. A high-speed camera captured ice specimen cracking initiation and propagation processes. The experimental results indicate that the overall initiation fracture toughness (IFT) of freshwater ice under dynamic loading exceeds that under quasi-static loading. The loading rate effect on the dynamic fracture toughness and failure modes greatly exceeds the test temperature effect. The freshwater ice dynamic IFT increases approximately linearly with the loading rate and rapidly at temperatures from –5°C to –45 °C. In all tests, cracks always initiate from the notch plane. Two symmetrical curved cracks then propagate from the contact end of two support rollers to the flat contact end, ultimately leading to different sample fragmentation distributions. These results improve the understanding of the dynamic fracturing mechanism in ice engineering applications.

The controlled synthesis of La 2 O 2 SO 4 :Eu 3+ nanofibres (NF) for luminescent applications is presented here for the first time. Three dimensional nanofibrous structures with average diameter of 90 nm were prepared successfully. Eu 3+ ions were further doped to study the luminescent property and phase structure. A strong red luminescence was obtained at the as-prepared NF. High asymmetry ratio (R) in the emission spectrum indicated that the Eu 3+ ions were located in a distorted cation environment and the luminescent NF obtained possessed a good colour purity. The emission intensity of the resulting NF varied with different Eu 3+ contents with the best emission brightness obtained at 20% Eu 3+ doping. An 18% improved luminescence decay time at a relative lower annealing temperature (650 °C) was obtained for the nanofibrous structure when compared to the corresponding bulk materials (BM). The quantum efficiency (QE) of the as-synthesised NF was found to be 6.3%, which was 17% enhanced from the QE of BM (5.4%). Oxidation activity of NF compared to BM was measured using Temperature-Programmed Reduction (TPR). The TPR peak temperature for the consumption of hydrogen was decreased 12% with the employment of NF, suggesting well improved oxygen storage capability of the resulting NF. Our results indicate the multifunctional applications of the resulting NF in different fields such as optics and oxygen storage.

In Arabidopsis, the CLAVATA3/EMBRYO SURROUNDING REGION-RELATED (CLE) peptides play important roles in regulating proliferation and differentiation of plant-specific stem cells. Although receptors of CLEs are reported to be leucine-rich repeat receptor kinases, the mechanisms underlying CLE-induced receptor activation remain largely unknown. Here we show that SOMATIC EMBRYOGENESIS RECEPTOR KINASEs (SERKs) serve as co-receptors in CLE41/TDIF-PXY signaling to regulate plant vascular development. TDIF induces interaction of its receptor PXY with SERKs in vitro and in vivo. Furthermore, the serk1-1 serk2-1 bak1-5 mutant plants are less sensitive to TDIF, phenocopying the pxy mutant with a compromised promotion of procambial cell proliferation. Crystal structure of the PXY-TDIF-SERK2 complex reveals that the last amino acid of TDIF conserved among CLEs and other evolutionary-related peptides is important for the interaction between SERK2 and PXY. Taken together, our current study identifies SERKs as signaling components of the TDIF-PXY pathway and suggests a conserved activation mechanism of CLE receptors.

Histone deacetylase (HDAC) inhibitors have demonstrated clinical benefits in subtypes of hematological malignancies. However, the efficacy of HDAC inhibitors in solid tumors remains uncertain. This study takes breast cancer as a model to understand mechanisms accounting for limited response of HDAC inhibitors in solid tumors and to seek combination solutions. We discover that feedback activation of leukemia inhibitory factor receptor (LIFR) signaling in breast cancer limits the response to HDAC inhibition. Mechanistically, HDAC inhibition increases histone acetylation at the LIFR gene promoter, which recruits bromodomain protein BRD4, upregulates LIFR expression, and activates JAK1-STAT3 signaling. Importantly, JAK1 or BRD4 inhibition sensitizes breast cancer to HDAC inhibitors, implicating combination inhibition of HDAC with JAK1 or BRD4 as potential therapies for breast cancer.

Purpose To determine the effectiveness of different interventions to slow down the progression of myopia in children. Methods We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov from inception to August 2014. We selected randomized controlled trials (RCTs) involving interventions for controlling the progression of myopia in children with a treatment duration of at least 1 year for analysis. Main Outcome Measures The primary outcomes were mean annual change in refraction (diopters/year) and mean annual change in axial length (millimeters/year). Results Thirty RCTs (involving 5422 eyes) were identified. Network meta-analysis showed that in comparison with placebo or single vision spectacle lenses, high-dose atropine (refraction change: 0.68 [0.52–0.84]; axial length change: −0.21 [−0.28 to −0.16]), moderate-dose atropine (refraction change: 0.53 [0.28–0.77]; axial length change: −0.21 [−0.32 to −0.12]), and low-dose atropine (refraction change: 0.53 [0.21–0.85]; axial length change: −0.15 [−0.25 to −0.05]) markedly slowed myopia progression. Pirenzepine (refraction change: 0.29 [0.05–0.52]; axial length change: −0.09 [−0.17 to −0.01]), orthokeratology (axial length change: −0.15 [−0.22 to −0.08]), and peripheral defocus modifying contact lenses (axial length change: −0.11 [−0.20 to −0.03]) showed moderate effects. Progressive addition spectacle lenses (refraction change: 0.14 [0.02–0.26]; axial length change: −0.04 [−0.09 to −0.01]) showed slight effects. Conclusions This network analysis indicates that a range of interventions can significantly reduce myopia progression when compared with single vision spectacle lenses or placebo. In terms of refraction, atropine, pirenzepine, and progressive addition spectacle lenses were effective. In terms of axial length, atropine, orthokeratology, peripheral defocus modifying contact lenses, pirenzepine, and progressive addition spectacle lenses were effective. The most effective interventions were pharmacologic, that is, muscarinic antagonists such as atropine and pirenzepine. Certain specially designed contact lenses, including orthokeratology and peripheral defocus modifying contact lenses, had moderate effects, whereas specially designed spectacle lenses showed minimal effect.

How we learn to interact with and understand our environment for the first time is an age-old philosophical question. Scientists have long sought to understand what is the origin of egocentric spatial localization and the perceptual integration of touch and visual information. It is difficult to study the beginnings of intermodal visual-motor and visual-tactile linkages in early infancy since infants' muscular strength and control cannot accurately guide visual-motor behavior and they do not concentrate well [1-6]. Alternatively, one can examine young children who have a restored congenital sensory modality loss. They are the best infant substitute if they are old enough for good muscle control and young enough to be within the classic critical period for neuroplasticity [7, 8]. Recovery studies after removal of dense congenital cataracts are examples of this, but most are performed on older subjects [9-14]. We report here the results of video-recorded experiments on a congenitally blind child, beginning immediately after surgical restoration of vision. Her remarkably rapid development of accurate reaching and grasping showed that egocentric spatial localization requires neural circuitry needing less than a half hour of spatially informative experience to be calibrated. 32 hr after first sight, she visually recognized an object that she had simultaneously looked at and held, even though she could not use single senses alone (vision to vision; touch to touch) to perform this recognition until the following day. Then she also performed intersensory transfer of tactile object experience to visual object recognition, demonstrating that the two senses are prearranged to immediately become calibrated to one another.

Dysfunction of the ubiquitin-proteasome system (UPS) and calcium homeostasis has been implicated in the neurodegeneration of Alzheimer's and Parkinson's diseases. The cytosolic calcium concentration is maintained by store-operated calcium entry (SOCE), which is repressed by Alzheimer's disease-associated mutants, such as mutant presenilins. We hypothesized that inhibition of UPS impacts SOCE. This study showed that pretreatment with sub-lethal levels of proteasome inhibitors, including MG-132 and clasto-lactacystin-β-lactone (LA), reduced SOCE after depletion of endoplasmic reticulum calcium in rat neurons. With the same treatment, MG-132 and LA reduced the protein levels of stromal interaction molecule 1and 2 (STIM1/2), but not the levels of Orai1 and canonical transient receptor potential channel 1 (TRPC1). STIM1 or STIM2 protein was mobilized to lysosome by MG-132/LA treatment as observed under an immunofluorescence confocal laser microscope. In the neurons, MG-132 and LA degraded p62/SQSTM1, promoted autophagy, converted LC3I to LC3II, and promoted co-localization of LC3 and lysosomes. Rapamycin, which enhances autophagy, reduced STIM1/2 protein levels, whereas bafilomycin, which inhibits autophagy, increased their protein levels. The protein levels of STIM1/2 and the amplitude of SOCE were decreased in SH-SY5Y with decreased protein level of proteasome subunit beta type-5 induced by shRNA. We conclude that sub-lethal levels of proteasome inhibition reduce SOCE and promote autophagy-mediated degradation of STIM1/2. UPS inhibition, a common finding in neurodegenerative diseases, interferes with calcium homeostasis via repression of SOCE.

Form deprivation myopia (FDM) is characterized by loss of choroidal thickness (ChT), reduced choroidal blood perfusion (ChBP), and consequently scleral hypoxia. In some tissues, changes in levels of peroxisome proliferator-activated receptor γ (PPARγ) expression modulate hypoxia-induced pathological responses. We determined if PPARγ modulates FDM through changes in ChT, ChBP, scleral hypoxia-inducible transcription factor (HIF-1α) that in turn regulate scleral collagen type 1 (COL1) expression levels in guinea pigs. Myopia was induced by occluding one eye, while the fellow eye served as control. They received daily peribulbar injections of either the PPARγ antagonist GW9662, or the GW1929 agonist, with or without ocular occlusion for 4 weeks. Ocular refraction and biometric parameters were estimated at baseline, 2 and 4 weeks post-treatment. ChT and ChBP were measured at the 2- and 4-week time points. Western blot analysis determined the expression levels of scleral HIF-1α and COL1. GW9662 induced a myopic shift in unoccluded eyes. Conversely, GW1929 inhibited FDM progression without affecting the refraction in unoccluded eyes. GW9662 reduced both ChT and ChBP in unoccluded eyes, while GW1929 inhibited their declines in occluded eyes. Scleral HIF-1α expression rose in GW9662-treated unoccluded eyes whereas GW1929 reduced HIF-1α upregulation in occluded eyes. GW9662 downregulated scleral COL1 expression in unoccluded eyes, while GW1929 reduced their decreases in occluded eyes. Therefore, PPARγ modulates collagen expression levels and FDM through an inverse relationship between changes in PPARγ and HIF-1α expression levels.

Background Myopia is a good model for understanding the interaction between genetics and environmental stimuli. Here we dissect the biological processes affecting myopia progression. Methods Human Genetic Analyses: (1) gene set analysis (GSA) of new genome wide association study (GWAS) data for 593 individuals with high myopia (refraction ≤ -6 diopters [D]); (2) over-representation analysis (ORA) of 196 genes with de novo mutations, identified by whole genome sequencing of 45 high-myopia trio families, and (3) ORA of 284 previously reported myopia risk genes. Contributions of the enriched signaling pathways in mediating the genetic and environmental interactions during myopia development were investigated in vivo and in vitro. Results All three genetic analyses showed significant enrichment of four KEGG signaling pathways, including amphetamine addiction, extracellular matrix (ECM) receptor interaction, neuroactive ligand-receptor interaction, and regulation of actin cytoskeleton pathways. In individuals with extremely high myopia (refraction ≤ -10 D), the GSA of GWAS data revealed significant enrichment of the HIF-1α signaling pathway. Using human scleral fibroblasts, silencing the key nodal genes within protein-protein interaction networks for the enriched pathways antagonized the hypoxia-induced increase in myofibroblast transdifferentiation. In mice, scleral HIF-1α downregulation led to hyperopia, whereas upregulation resulted in myopia. In human subjects, near work, a risk factor for myopia, significantly decreased choroidal blood perfusion, which might cause scleral hypoxia. Interpretation Our study implicated the HIF-1α signaling pathway in promoting human myopia through mediating interactions between genetic and environmental factors. Funding National Natural Science Foundation of China grants; Natural Science Foundation of Zhejiang Province.

Retinoblastoma (Rb) is the most prevalent intraocular malignant tumour in children with survival rate less than 30% globally. Its developmental origin and drug agents remain largely unexplored. Here, we developed the first organoid Rb model derived from human embryonic stem cells (hESCs) with a biallelic knockout (RB1-/-) or mutagenesis (RB1Mut/Mut). These organoid retinoblastomas exhibit extremely consistent properties of Rb tumourigenesis, transcriptome, and genome-wide methylation. We found Rb originated from ARR3+ maturing cone precursors during development and a new unfolded protein response cell type. A key PI3K-Akt pathway was aberrantly regulated, and its activator SYK was significantly upregulated. Furthermore, the SYK inhibitors induced a more significant therapeutic response from early-stage organoid Rb. In conclusion, we established a novel organoid Rb model derived from human ESCs in a dish and discovered its cell-of-origin and potential drug agents, thus shedding light on the development and therapeutics of other human cancers.

Genetic etiology of congenital/infantile nystagmus remains largely unknown. This study aimed to identify genomic mutations in patients with infantile nystagmus and an associated disease network. Patients with inherited and sporadic infantile nystagmus were recruited for whole-exome and Sanger sequencing. β-Mannosidase activities were measured. Gene expression, protein–protein interaction, and nystagmus-associated lysosomal storage disease (LSD) genes were analyzed. A novel heterozygous mutation (c.2013G>A; p.R638H) of MANBA, which encodes lysosomal β-mannosidase, was identified in patients with autosomal-dominant nystagmus. An additional mutation (c.2346T>A; p.L749H) in MANBA was found by screening patients with sporadic nystagmus. MANBA was expressed in the pretectal nucleus of the developing midbrain, known to be involved in oculomotor and optokinetic nystagmus. Functional validation of these mutations demonstrated a significant decrease of β-mannosidase activities in the patients as well as in mutant-transfected HEK293T cells. Further analysis revealed that nystagmus is present in at least 24 different LSDs involving the brain. This is the first identification of MANBA mutations in patients with autosomal-dominant nystagmus, suggesting a new clinical entity. Because β-mannosidase activities are required for development of the oculomotor nervous system, our findings shed new light on the role of LSD-associated genes in the pathogenesis of infantile nystagmus. Genet Med 17 12, 971–979.

A simple and facile method for multiscale, in-plane patterning of graphene oxide and reduced graphene oxide (GO–rGO) was developed by region-specific reduction of graphene oxide (GO) under a mild irradiation. The UV-induced reduction of graphene oxide was monitored by various spectroscopic techniques, including optical absorption, X-ray photoelectron spectroscopy (XPS), Raman, and X-ray diffraction (XRD), while the resultant GO–rGO patterned film morphology was studied on optical microscope, scanning electron microscope (SEM), and atomic force microscope (AFM). Flexible symmetric and in-plane supercapacitors were fabricated from the GO–rGO patterned polyethylene terephthalate (PET) electrodes to show capacitances up to 141.2 F/g.

In studies on dry eye (DE) disease, an association has been identified between tear film hyperosmolarity and inflammation severity elicited through receptor-induced increases in proinflammatory cytokine and chemokine release. These immune reactions might be mediated by inflammasomes, macromolecular complexes mounted around the NLRP3 protein and can be activated by reactive oxygen species (ROS) over-generation. Hence in this study we determine whether: a) ROS activated NLRP3 inflammasomes mediate hyperosmotic stress-induced inflammation in human corneal epithelial cells (HCECs); b) the ROS-NLRP3-IL-1β axis activation is associated with environment-induced DE. Immortalized HCECs were exposed to 500 mOsm medium in the presence and absence of a ROS inhibitor, N-acetyl-l-cysteine (NAC). HCECs transfected with NLRP3 siRNA or a negative control (NC) siRNA. Intracellular ROS was measured by fluorometric analysis using the probe 2',7'-dichlorofluorescin diacetate (DCFH-DA). Real-time PCR evaluated NLRP3, ASC, pro-caspase-1 and pro-IL-1β mRNA levels. Western blot analysis assessed NLRP3 protein expression whereas caspase-1 activity was determined with a fluorometric assay. Bioactive IL-1β release was assessed by ELISA. ROS production, NLRP3 inflammasome and pro-IL-1β gene expression as well as IL-1β secretion were also evaluated in the conjunctival epithelial cells and tear fluid samples of environment-induced DE patients and normal subjects. NAC suppressed hyperosmolarity-induced rises in ROS levels, NLRP3 inflammasome formation and activation, caspase-1 activity and IL-1β release. On the other hand, NLRP3 siRNA knockdown inhibited hyperosmotic stress-induced NLRP3 activation, which led to ASC, pro-caspase-1 and pro-IL-1β mRNA down-regulation followed by suppression of associated caspase-1 activity and IL-1β secretion. In addition, in ocular surface samples of environment-induced DE patients, ROS generation, NLRP3, ASC, pro-caspase-1 and pro-IL-1β gene expression as well as IL-1β secretion were upregulated. Taken together, NLRP3 mediated innate immune responses triggered by rises in ROS generation induce inflammation in hyperosmotic stressed HCECs. ROS-NLRP3-IL-1β signaling pathway might play a priming role in environment-induced DE development.

The transcription factor Otx1 is specifically expressed in layer V pyramidal cells (L5PCs) in the cerebral cortex. Otx1 null mutant mice have a defect in the developmental axon pruning of L5PCs and show epileptic seizures. However, the role of Otx1 in electrophysiology, morphology and synaptology of the cortical neurons has not been fully investigated. This study examines the influences of Otx1 on neuronal properties of L5PCs by loss- and gain-of-function approaches. Mice with an Otx1-null mutation had decreased structural measurements of basal dendrites in L5PCs. In contrast, the size of basal dendrites was increased in the Otx1-over-expressed pyramidal cells (PCs) in L2/3 where the gene normally does not express. PCs showed burst and non-burst firing patterns of action potentials. The proportion of burst firing neurons was reduced in the Otx1 mutant but increased in the neurons over-expressing Otx1. Although the burst firing population decreased, the proportion of those bursting neurons with a low threshold increased in the Otx1 mutant mice. Moreover, excitatory facilitating synaptic connections formed between L5PCs were predominant in the Otx1 mutant mice, which greatly contrasted with the predominant depressing synaptic connections in the controls. Taken together, it suggests an enhanced activity of neuronal network in the cortex of Otx1 mutant mice. These data indicate that the Otx1 expression is essential for the normal development of dendritic morphology, intrinsic electrophysiology and synaptic dynamics of L5PCs. This study provides new insights into molecular mechanisms underlying the spatial and temporal regulation of neuronal and synaptic properties of L5PCs, and improves our understanding on the generation of epileptic seizures.

The proliferation and differentiation of adult stem cells must be tightly controlled in order to maintain resident tissue homeostasis. Dysfunction of stem cells is implicated in many human diseases, including cancer. However, the regulation of stem cell proliferation and differentiation is not fully understood. Here we show that the sterile-like 20 kinase, Tao, controls tissue homeostasis by regulating the Hippo pathway in the Drosophila adult midgut. Depletion of Tao in the progenitors leads to rapid intestinal stem cell (ISC) proliferation and midgut homeostasis loss. Meanwhile, we find that the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling activity and cytokine production are significantly increased, resulting in stimulated ISC proliferation. Furthermore, expression of the Hippo pathway downstream targets, Diap1 and bantam, is dramatically increased in Tao knockdown intestines. Consistently, we show that the Yorkie (Yki) acts downstream of Tao to regulate ISC proliferation. Together, our results provide insights into our understanding of the mechanisms of stem cell proliferation and tissue homeostasis control.

Water is the most abundant molecule in almost all living organisms. Aquaporins are channel proteins that play critical roles in controlling the water content of cells. Here, we report the identification of an AP2/EREBP family transcription factor in Arabidopsis thaliana, TRANSLUCENT GREEN (TG), whose overexpression in transgenic plants gave enhanced drought tolerance and vitrified leaves. TG protein is localized in the nucleus, binds DRE and GCC elements in vitro, and acts as a transcriptional activator in yeast cells. Microarray analysis revealed a total of 330 genes regulated by TG, among which five genes encode aquaporins. A transient expression assay showed that TG directly binds to the promoters of three aquaporin genes, such as AtTIP1;1, AtTIP2;3, and AtPIP2;2, indicating that TG directly regulates the expression of these genes. Moreover, overexpression of AtTIP1;1 resulted in vitrified phenotypes in transgenic Arabidopsis plants, similar to those observed in TG overexpression lines. Water injection into wild-type leaves recapitulated the vitrified leaf phenotypes, which was reversed by cutting off the water supply from vascular bundles. Taken together, our data support that TG controls water balance in Arabidopsis through directly activating the expression of aquaporin genes.

Prediction of unobserved microRNA (miRNA)-disease associations is one of the most important research fields due to miRNA’s roles of diagnostic biomarkers and therapeutic targets for large number of human complex diseases. Thus, the development of effective computational methods for identification of novel miRNA-disease associations would provide a unique opportunity to design better therapeutic interventions. In this study, we presented a novel computational model named Matrix Decomposition and Label Propagation for MiRNA-Disease Association prediction (MDLPMDA) by integrating known miRNA-disease associations, disease semantic similarity, miRNA functional similarity, and Gaussian interaction profile kernel similarity for miRNAs and diseases. Based on the new adjacency matrix of miRNA-disease associations obtained from matrix decomposition through sparse learning method, the model is presented by implementing label propagation process on the constructed integrated miRNA similarity network and integrated disease similarity network, respectively, and then using an average ensemble strategy to combine the two different prediction models. At last, AUCs of 0.9222 and 0.8490 in global and local leave-one-out cross-validation (LOOCV) proved the model’s reliable performance. In addition, AUC of 0.9211+/-0.0004 in 5-fold cross-validation confirmed its accuracy and stability. We further implemented case studies to predict potential miRNAs associated with human complex diseases based on different versions of HMDD database. We also carried out case studies on diseases without any known related miRNAs to examine the prediction performance of MDLPMDA. At last, the analysis of the assessment results of cross validations and case studies indicated that MDLPMDA could be an effective method to infer novel miRNA-disease associations.

ABC1Ks (activity of bc1 complex kinases) are atypical protein kinases that do not display many of the typical eukaryotic protein kinase features. Most ABC1K members have been demonstrated to localize in chloroplasts or mitochondria and regulation of quinone synthesis is the ancestral function of ABC1Ks (Lundquist et al., 2012a). The ABC1K gene family is evolutionarily conserved and has greatly expanded in photosynthetic organisms. In Arabidopsis, the ABC1K family consists of 17 members, eight of which are predicted to localize to chloroplasts.

It was recently demonstrated that chromaticity could affect eye growth and refractive development in guinea pigs but it remained unclear whether correction with spectacle lenses could balance these effects and how retinal responses change with different spectral compositions of light. Three illumination conditions were tested: blue, red and white light. Animals were raised without or with monocular spectacle lenses from three to seven weeks of age. Luminance electroretinograms (ERGs) were recorded to explore retinal responses with the different spectral compositions. In our special colony of pigmented guinea pigs, characterized by residual hyperopia, spontaneous myopia and poor emmetropization, red light induced early thinning of the choroid and relative myopia, compared to white light. Effects of red light could not be suppressed if positive spectacle lenses were worn. ERGs showed that red light failed to elicit robust retinal responses. Blue light inhibited axial eye growth, even when animals were reared with negative lenses. Intensity-matched blue and white light elicited similar a-waves but different b-waves, suggesting that the wavelength of light affects visual control of eye growth through different processing in the inner retina. We hypothesize that blue light might stimulate preferentially the ON pathway to inhibit myopia induced by negative lenses, at least in guinea pigs.