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David A Ammar,1 Eric Porteous,2 Malik Y Kahook3 1Research Department, Lions World Vision Institute, Tampa, FL, USA; 2New World Medical, Rancho Cucamonga, CA, USA; 3Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, CO, USACorrespondence: Malik Y Kahook, Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA, Tel +1 720 848 2501, Email Malik.Kahook@cuanschutz.eduPurpose: To evaluate incisional or excisional tissue-level effects of ab interno goniotomy techniques on human trabecular meshwork (TM).Methods: The TM from human cadaveric corneal rim tissue was treated using three devices: (1) Kahook Dual Blade (KDB) GLIDE, (2) iAccess, and (3) SION. Two human corneal rims were used for each of the iAccess and SION devices and one with the KDB GLIDE, with 360 degrees of TM treated in each case. Sections were then prepared for analysis and comparison between devices. Tissue samples underwent standard histologic processing with H&E stain, followed by comparative analyses.Results: Areas treated with the KDB GLIDE device resulted in nearly complete excision of TM overlying the canal of Schlemm without injury to surrounding tissues. The iAccess device can be used as a focal trephine to create holes or dragged for TM disruption. When used to create holes, iAccess punched through the full thickness of the TM and also disrupted the anterior scleral tissue. It caused some incisional openings through the TM but with significant leaflets remaining and minimal true “hole-punch” effect. When the device tip was dragged, iAccess incised the TM and left debris behind with little, if any, excision of tissue. SION led to both incision and excision of TM with incision predominating over excision.Conclusion: The various methods evaluated to perform ab interno goniotomy resulted in varying degrees of TM incision or excision. Only the KDB GLIDE device resulted in reliable excision of TM, while the other devices produced incision or minimal excision of tissue with residual leaflets and debris. Use of iAccess resulted in focal disruption of the anterior scleral wall. Because incisional approaches that leave longer residual leaflets may be more prone to fibrosis and closure compared to excisional treatments, clinical correlation will be necessary to better understand the significance of these findings with respect to relative effectiveness of intraocular pressure lowering in eyes with glaucoma.Keywords: glaucoma, goniotomy, excision, incision, trabecular meshwork

David A Ammar,1 Leonard K Seibold,2 Malik Y Kahook2 1Research Department, Lions Eye Institute for Transplant & Research, Tampa, FL, USA; 2Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO, USACorrespondence: Malik Y KahookUniversity of Colorado School of Medicine, 1675 Aurora Ct, Aurora, CO 80045, USATel +1 720 848 2500Fax +1 720 848 5014Email malik.kahook@cuanschutz.eduPurpose: To evaluate the tissue-level effects of goniotomy techniques on human trabecular meshwork (TM).Design: Laboratory investigation.Methods: The TM from human cadaveric corneal rim tissue was treated using 4 techniques: (1) microvitreoretinal (MVR) blade; (2) 360° trabeculotomy with 5-0 prolene suture; (3) the Kahook Dual Blade (KDB) Glide® device; (4) TrabEx™ device; tissue samples underwent standard histologic processing with H&E stain followed by comparative analyses.Results: The MVR blade exhibited incision of TM extending into the scleral wall. The TrabEx device removed a small portion of TM with large leaflet tissue remnants in all treated areas. 360° suture trabeculotomy resulted in incision of the TM proximate to Schwalbe’s line with no excised tissue evident in all treated areas. Areas treated with the KDB Glide device resulted in nearly complete excision of TM without injury to surrounding tissues.Conclusion: The various methods used for performing goniotomy or trabeculotomy resulted in varying degrees of incision or excision of TM. Only the KDB Glide device resulted in reliable excision of TM with the other devices producing incision or variable excision of tissue. Clinical correlation is required to better understand the implications of the current findings when using these methods to lower intraocular pressure in eyes with glaucoma.Keywords: glaucoma, goniotomy, trabecular meshwork

تعتبر أنظمة التناضح العكسي من الأنظمة الفعالة في عملية تنقية المياه التي تخدم في مجالات شتى. تعد النماذج التجريبية نهجاً مكلفاً ويستغرق وقتاً طويلاً لدراسة أنظمة أغشية التناضح العكسي بينما يظهر استخدام النماذج الحاسوبية القائمة على البرمجيات كطريقة بديلة للتنبؤ بأداء الغشاء، من أجل التنبؤ بقيم المواد المنحلة الكلية المستقبلية تم إنشاء نموذج من الشبكات العصبونية الصناعية ANN باستخدام برنامج MATLAB، حيث تم قطف العينات وتحليلها فيزيائياً وكيميائياً وذلك للمياه الخام والمياه الناتجة عن المحطة في حالة الدراسة وهي محطة معالجة المياه في شركة حميشو للمعادن، تم قياس بارامترات مؤثرة على قيمة المواد المنحلة الكلية الخارجة وهي (درجة الحرارة، درجة الحموضة، الضغط، المواد المنحلة الكلية) للمياه الداخلة و الخارجة من المحطة ثم تم انشاء نموذج من الشبكات العصبونية الصنعية من نوع Neural Net fitting، أظهرت النتائج قدرة النموذج على التنبؤ بكفاءة قدرها R=0.97 وذلك بالمقارنة ما بين القيم المحسوبة والمقاسة.

Lung cancer is frequently detected in an advanced stage and has an unfavourable prognosis. Conventional therapies are ineffective for the treatment of metastatic lung cancer. While certain molecular targets have been identified as having a positive response, the absence of appropriate drug carriers prevents their effective utilization. Lung cancer cell-derived exosomes (LCCDEs) have gained attention for their involvement in the development of cancer, as well as their potential for use in diagnosing, treating, and predicting the outcome of lung cancer. This is due to their biological roles and their inherent ability to transport biomolecules from the donor cells. Lung cancer-associated cell-derived extracellular vesicles (LCCDEVs) have the ability to enhance cell proliferation and metastasis, influence angiogenesis, regulate immune responses against tumours during the development of lung cancer, control drug resistance in lung cancer treatment, and are increasingly recognised as a crucial element in liquid biopsy evaluations for the detection of lung cancer. Therapeutic exosomes, which possess inherent intercellular communication capabilities, are increasingly recognised as effective vehicles for targeted drug delivery in precision medicine for tumours. This is due to their exceptional biocompatibility, minimal immunogenicity, low toxicity, prolonged circulation in the bloodstream, biodegradability, and ability to traverse different biological barriers. Currently, multiple studies are being conducted to create new means of diagnosing and predicting outcomes using LCCDEs, as well as to develop techniques for utilizing exosomes as effective carriers for medication delivery. This paper provides an overview of the current state of lung cancer and the wide range of applications of LCCDEs. The encouraging findings and technologies suggest that the utilization of LCCDEs holds promise for the clinical treatment of lung cancer patients.

The pecan tree holds significant economic value due to its versatile cultivation and utilization. To expand its reach in global markets, pecan nut breeding aims to enhance both the quantity and quality of the product through meticulous planning. In this context, phosphorus and zinc are crucial nutrients for pecan nuts, playing a notable role in their nutritional profile. An experiment was conducted to investigate the effects of different levels of phosphorus and zinc on the nutrient content and yield of pecan trees. The experiment was designed in a factorial form with three levels of phosphorus (0, 250, and 500 kg P2O5 ha-1) and three levels of zinc (0, 25, and 50 kg Zn ha-1) in four replications. The results of the experiment showed that increasing the consumption of phosphorus had a significant effect on the concentration of phosphorus and iron in the leaves. However, a higher level of phosphorus application reduced the concentration of copper in the leaves. Similarly, the application of zinc increased the concentration of zinc (from 138.54 to 166.25 mg kg-1) in the leaves but decreased the concentration of phosphorus (from 0.15% to 0.13%). Interestingly, the application of 250 kg ha-1 of phosphorus led to a significant increase in the dry weight of the kernel, while higher levels of phosphorus had the opposite effect. These findings suggest that careful management of phosphorus and zinc levels in pecan orchards can have a significant impact on both nutrient content and yield. This research provides valuable insights for pecan breeders and growers seeking to optimize their practices and improve the quality of their crops.

Security concerns in residential and working environments are more critical than ever, yet traditional door locks that rely on physical keys still hold significant vulnerabilities. Those key risks include loss, misplacement, or copying and may result in unauthorized access. Moving into Industry 4.0, there is great potential to integrate IoT technology to create a far more sophisticated and resilient door access system to handle such concerns. This paper analyze the design and development of a new IoT-based smart lock system enhancing security with fingerprint recognition, RFID technology, and application control via Wi-Fi as an additional to conventional lock such as kill switch and also front desk switch. In the discussed system, the ESP8266 microcontroller is used for wireless communication. Then, Virtuino IoT applications provided the function for real-time monitoring, while HiveMQ MQTT broker secured data transmissions. Therefore, the electromagnetic locking mechanism at the door was improved by using multi-layer access control. As mentioned, the methodology would provide an integration of critical hardware parts, such as NodeMCU ESP8266, Arduino Uno and electromagnetic locks, with robust software solutions in terms of secure communication and control. Once developed, the system architecture will be simulated and tested for its effectiveness in achieving better security and operational efficiency. The opted multi-layered security system can be beneficial to residential and working environment and is designed to overcome the limitations of conventional locks. Thus, enhancing the implementation of IoT-based security solutions in everyday life.

Pecan fruit, also known as pecan nut, is a type of nut that is popular for its rich, buttery flavor and crunchy texture. This research aimed to investigate the effects of spraying boric acid and zinc sulfate on the physical traits of pecan fruit in Erbil, Iraq. The experiment was conducted in the spring of 2022 using a completely randomized block design with three levels of boric acid (0, 1500, and 3000 mg l-1) and three levels of zinc sulfate (0, 2500, and 5000 mg l-1). The spraying was carried out before the flower buds opened, and at the time of harvesting, various physical characteristics of the fruit were measured, including length, width, weight, kernel weight, percentage of hull, percentage of shell, percentage of kernel, and absorption of elements in leaves and nuts. The results showed that spraying with boric acid (3000 mg l-1) and zinc sulfate (5000 mg l-1) had the greatest effect on increasing fruit length, while the fruit width was highest in the zinc treatment (5000 mg l-1), and it was significant compared to the control treatment. None of the treatments had a significant effect on fruit weight, kernel weight, percentage of shell, and percentage of hull skin. Moreover, the spraying significantly increased the amount of boron and zinc elements in leaves and nuts. Therefore, it can be concluded that spraying with boric acid and zinc sulfate can be an effective method to improve the physical characteristics of pecan nuts and increase the absorption of essential elements in leaves and nuts.

The Geographic Information System (GIS) is one of the modern database software which is used to collect, analyze, display, processing and produce geographic information maps for a specific objective. In addition, a statistical analysis can be generated within GIS on specific data to produce quantitative results. In this study, the GIS utilized to produce thematic maps showing the variation of bearing capacity of shallow foundation in Al-Basrah province soil. All the features mentioned above illustrate the importance of GIS exploring more valuable results such as the bearing capacity of shallow foundation from the results of standard penetration tests (SPT) conducted in Al-Basrah province soil. The total number of boreholes drilled was 135 distributed irregularly in the study area. In each borehole, three SPTs were performed at depths of 1.5, 6, and 9.5 m measured from the existing ground level (EGL). The results of the study can be summarized by the production of thematic maps showing the variation of the bearing capacity of the soil over the whole area of Al-Basrah city correlated with several depths. These maps can be used by different local authorities to predict soil bearing capacity and choose a suitable type of foundation. In addition, it can be utilized to assess the foundations of existing and irregularly constructed buildings and to assess the extent of the risks of failure and collapse.

Successfully, theoretical equations were established to study the effect of solvent polarities on the electron current density, fill factor and efficiencies of Tris (8-hydroxy) quinoline aluminum (Alq3)/ ZnO solar cells. Three different solvents studied in this theoretical works, namely 1-propanol, ethanol and acetonitrile. The quantum model of transition energy in donor–acceptor system was used to derive a current formula. After that, it has been used to calculate the fill factor and the efficiency of the solar cell. The calculations indicated that the efficiency of the solar cell is influenced by the polarity of solvents. The best performance was for the solar cell based on acetonitrile as a solvent with electron current density of (5.078-12.331) mA/cm2between (1-6) V. In addition, the highest efficiency calculated for the (Alq3)/ ZnO solar cell was 2.593% which corresponds to the highest current density. However, the calculated fill-factor values were significantly unchanged with the changing of the current density. Interestingly, the measured values are in a good agreement with previously reported experimental values.

Clarias batrachus is a commercially important food fish. In the present study, effect of varying dietary protein levels was evaluated on the survival, growth parameters and proximate composition of C. batrachus. Diets comprising 25%, 30%, 35%, 40%, 45%, and 50% crude protein (CP) were supplied to fish in T1, T2, T3, T4, T5, and T6, respectively, at the rate of 5% of fish body weight for the entire 90 days, twice daily. Size of each stocked C. batrachus was recorded after 15 days. Results revealed 100% survival rate of C. batrachus in all treatments. Significantly highest (P

Edge computing is used with cloud computing as an extension to increase the performance of delay-sensitive applications such as autonomous vehicles, healthcare systems, video surveillance systems, ..etc. The fast increase in the Internet of Things (IoT) devices increases the amount of data transferred in the network. IoT devices are resource-constrained in terms of energy consumption and computation capability. Data processing near IoT devices enabled by edge devices. Hence reduces the transmission power of sending data to the cloud and causes delays due to the cloud being placed far away from the devices. Most real-time applications depend on artificial intelligence (AI) techniques, increasing the computations on IoT-edge devices. Conversely, if this AI workload is executed on the cloud, the delay increase causes degradation in application performance. How to decide where the computation is done in an IoT, edge and cloud network is an important issue. The purpose of optimizing the workload allocation decision is to increase the application performance in terms of Quality of Experience (QoE) and Quality of Service (QoS); hence, the major goal is to reduce the delay time while maintaining the accuracy of the AI systems. As presented in this review, many researchers focus on proposing a workload allocation decision based on AI techniques. In contrast, other research focuses on the AI workload, hence presenting a method for partitioning the AI model to increase the system's accuracy in the resource constraint devices (end device and edge server). Many other researches also used the AI model for resource allocation and provisioning between edge servers and the cloud. In this review, the integration between AI and edge–cloud environment is investigated, the AI workload allocation methods are presented and analyzed, a brief overview of the application of deep learning in edge-cloud computing is also presented, and many challenges that need to be addressed for the AI application are discussed. Many issues and challenges are also presented for optimizing the edge.

Abstract. With the rapid spread of technology in all sectors of life and the necessary need to increase the speed of payment processes, confidentiality, and privacy in business operations, cryptocurrencies appeared. The cryptocurrency is a virtual and intangible currency, in which transactions are made through the Internet and without any physical exchange between parties. These currencies are characterized by decentralization, transparency, privacy. Because transactions are carried out through a cryptography process and depend on Blockchain technology it is highly protected. Blockchain generally is a distributed ledger or a decentralized database. The Blockchain architecture combines advanced cryptography, distributed consensus mechanisms, and a complex system of incentives and rewards. In cryptocurrency, transactions are created, transferred, and verified through an integrated process called mining. Network members (network nodes) who carry out verification processes of transactions are called miners. As it is a credit or debit card used in banking transactions, in cryptocurrencies there is a so-called electronic wallet that is used for transactions that take place on cryptocurrencies over the Internet through computers or smartphones. Blockchain technology architecture has given cryptocurrencies many advantages and features that increase its strength and distinction from regular currencies and regular financial transactions such as decentralization, high confidentiality, anonymity, speed of transactions, very low fees, unlimited number of transactions, unrestricted by geography and borders, transparency, protection from Inflation, and the peer-to-peer network. The misuse of powerful features in cryptocurrencies and Blockchain technology has led to many disadvantages such as the risks of lack of knowledge, the lack of wide acceptance, the high risk of investing in them, its volatile nature, and the inability to return missing payments. This study concentrates on cryptocurrencies in terms of advantages and disadvantages.

Abstract— Globalization on one end has increased urbanization but on the other extreme was a major parameter of depletion of non-renewable resources. United Nation as a custodian of human rights has provided a long-term strategy of sustainability-Vision 2030 a long-term perspective that was initiated in 2015 having 17 sustainable development goals (SDGs) constituting 169 global targets related to the SDGs with a focus to improve the social, economic and environmental concerns of a human being”. Sustainable building of cities and communities is its 11th SDG. This paper provides a sound basis to use building performance simulation (BPS) in buildings to reduce the level of energy consumption in Saudi Arabia (KSA). A Survey was conducted evaluating the knowledge of BPS around the construction community along with a case study that is done to analyze the impact of BPS on overall energy efficiency. The results reveal a mixed knowledge level of the audience where most people are unaware of BPS and the professionals also have a very diminutive knowledge of this. However, it was observed that BPS has wide applications in building design as 50% energy efficiency is achieved as compared with the traditional approach of designing. The study discloses the fact of boosting up a country’s economy by application of BPS as it lowers the energy consumption and carbon footprints. Moreover, a relationship of BPS with customer satisfaction and a framework for implementing sustainability in architectural projects are also suggested.

BackgroundMore cancer survivors and a greater burden of long-term side effects have resulted from rising cancer incidence, improved treatment modalities, and younger age at cancer diagnosis. Treatment- related Infertility (TRI) is a well-known sequelae. This study looked at current oncofertility support and fertility preservation (FP) in men and women of reproductive age with cancer in Saudi Arabia, where there is little knowledge on the subject.MethodsA cross-sectional study included oncology patients of reproductive age from an academic hospital was conducted. Patients' characteristics, cancer type, treatment modalities and assessment of oncofertility support data were collected and examined to assess oncofertility support and potentially influencing factors.ResultsOur study included 135 patients (39.3% males and 60.7% females). Although 66.7% believed they were fertile at the time of diagnosis, and more than half planned to have children in the future, Unfortunately, only 37.8% have received fertility counseling, and only 17% have seen a fertility specialist. In male patients, the most common FP method was sperm cryopreservation (6.7%), while the majority of both genders (87.4%) did not use any FP method. Two-thirds of the patients are knowledgeable about TRI and FP methods. About half of the female patients (57.3%) were advised about the possibility of post-treatment amenorrhea while only 8.1% of the whole cohort received psychological support.ConclusionsDespite patients' satisfactory knowledge of TRI and FP, oncologists infrequently referred their patients to a specialized fertility service. More than half of our patients expressed a desire to have children in the future, but this desire was impeded by limited oncofertility care and FP procedures. Several factors influenced the knowledge of TRI, fertility counseling and FP. It is critical to incorporate oncofertility into management planning as it has a significant impact on patients' quality of life.

Department of Periodontics, School of Stomatology, Lanzhou University, Lanzhou, China. Department of Periodontics, Faculty of Dentistry, Thamar University, Dhamar, Yemen.

Quantum computers are believed to have the ability to process huge data sizes, which can be seen in machine learning applications. In these applications, the data, in general, are classical. Therefore, to process them on a quantum computer, there is a need for efficient methods that can be used to map classical data on quantum states in a concise manner. On the other hand, to verify the results of quantum computers and study quantum algorithms, we need to be able to approximate quantum operations into forms that are easier to simulate on classical computers with some errors. Motivated by these needs, in this paper, we study the approximation of matrices and vectors by using their tensor products obtained through successive Schmidt decompositions. We show that data with distributions such as uniform, Poisson, exponential, or similar to these distributions can be approximated by using only a few terms, which can be easily mapped onto quantum circuits. The examples include random data with different distributions, the Gram matrices of iris flower, handwritten digits, 20newsgroup, and labeled faces in the wild. Similarly, some quantum operations, such as quantum Fourier transform and variational quantum circuits with a small depth, may also be approximated with a few terms that are easier to simulate on classical computers. Furthermore, we show how the method can be used to simplify quantum Hamiltonians: In particular, we show the application to randomly generated transverse field Ising model Hamiltonians. The reduced Hamiltonians can be mapped into quantum circuits easily and, therefore, can be simulated more efficiently.

Differential settlement is a common problem in the bridge-roadway transition zone. Approach slabs are often constructed to mitigate the uneven settlement in this problematic zone. An appropriate simulation of the dynamic response of moving loads, approach slab and soil materials is necessary for realistic results. In the present study, the performance of the slab under traffic flow is investigated by a 3D dynamic analysis. For this purpose, the slab is modelled as a plate element while Mohr-Coulomb material model is adopted for base, subbase and subgrade soils. A number of parameters were considered to study the sensitivity of the proposed model to some soil, slab and moving load parameters that contribute to the behaviour of the approach slab. The main variables investigated in this study were the slab thickness, the restriction condition of the slab, the subgrade stiffness, weight of the passing vehicles and the analysis method adopted in such problems. Analysis results including predicted deformations and slab bending moments provide engineers with the necessary engineering knowledge to understand the response of approach slabs under different conditions.

Type-2 diabetes is a growing lifestyle disease mainly due to increasing physical inactivity but also associated with various other variables. In Saudi Arabia, around 58.5% of the population is deemed to be physically inactive. Against this background, this study attempts explore the spatial heterogeneity of Type-2 diabetes prevalence in Jeddah and to estimate various socio-economic and built environment variables contributing to the prevalence of this disease based on modelling by ordinary least squares (OLS), weighted regression (GWR) and multi-scale geographically weighted (MGWR). Our OLS results suggest that income, population density, commercial land use and Saudi population characteristics are statistically significant for Type-2 diabetes prevalence. However, by the GWR model, income, commercial land use and Saudi population characteristics were significantly positive while population density was significantly negative in this model for 70.6%, 9.1%, 26.6% and 58.7%, respectively, out of 109 districts investigated; by the MGWR model, the corresponding results were 100%, 22%, 100% and 100% of the districts. With the given data, the corrected Akaike information criterion (AICc), the adjusted R2, the log-likelihood and the residual sum of squares (RSS) indices demonstrated that the MGWR model outperformed the GWR and OLS models explaining 29% more variance than the OLS model, and 10.2% more than the GWR model. These results support the development of evidence-based policies for the spatial allocation of health associated resources for the control of Type-2 diabetes in Jeddah and other cities in the Arabian Gulf.

Dentists could fail to notice periapical lesions (PLs) while examining panoramic radiographs. Accordingly, this study aimed to develop an artificial intelligence (AI) designed to address this problem. Materials and methods: a total of 18618 periapical root areas (PRA) on 713 panoramic radiographs were annotated and classified as having or not having PLs. An AI model consisting of two convolutional neural networks (CNNs), a detector and a classifier, was trained on the images. The detector localized PRAs using a bounding-box-based object detection model, while the classifier classified the extracted PRAs as PL or not-PL using a fine-tuned CNN. The classifier was trained and validated on a balanced subset of the original dataset that included 3249 PRAs, and tested on 707 PRAs. Results: the detector achieved an average precision of 74.95%, while the classifier accuracy, sensitivity and specificity were 84%, 81% and 86%, respectively. When integrating both detection and classification models, the proposed method accuracy, sensitivity, and specificity were 84.6%, 72.2%, and 85.6%, respectively. Conclusion: a two-stage CNN model consisting of a detector and a classifier can successfully detect periapical lesions on panoramic radiographs.

تهدف هذه الدراسة لتحضير مضغوطات ديكلوفيناك الصوديوم مطولة التحرر بتقنية التلبيس بالطبقة الرقيقة (الفلم) وذلك نظراً للمزايا المتعددة للأشكال الصيدلانية مطولة التحرر. حُضِرت عدة صيغ باستخدام الإيتيل سليلوز كبلمر بتركيز 5% في الكحول. قُيمت الخصائص المختلفة للحثيرات قبل الضغط، وكذلك خصائص المضغوطات قبل وبعد التلبيس. دُرس تأثير العوامل المختلفة خلال عملية التلبيس على تحرر ديكلوفيناك الصوديوم من المضغوطات الملبسة كتأثير سماكة التلبيس، تأثير الملدن (زيت السيليكون) بالإضافة إلى التركيز الذي يستخدم به، وتأثير وجود المادة المالئة ونوعها (التالك أو شمعات المغنزيوم). أظهرت النتائج أن تحرر ديكلوفيناك الصوديوم يقل بزيادة سماكة طبقة التلبيس، وبوجود الملدن الكاره للماء وزيادة تركيزه، وبوجود وطبيعة المادة المالئة. كما أن تحرر ديكلوفيناك الصوديوم من المضغوطات الملبسة كان بآليتي الاسترخاء والانتشار، وقد تم التحرر وفقاً لنموذج Higuchi في معظم الصيغ.

Chronic immune activation and inflammation are unwanted consequences of many pathological conditions, since they could lead to tissue damage and immune exhaustion, both of which can worsen the pathological condition status. In fact, the immune system is naturally equipped with immunoregulatory cells that can limit immune activation and inflammation. However, chronic activation of downregulatory immune responses is also associated with unwanted consequences that, in turn, could lead to disease progression as seen in the case of cancer and chronic infections. Myeloid-derived suppressor cells (MDSCs) are now considered to play a pivotal role in the pathogenesis of different inflammatory pathological conditions, including different types of cancer and chronic infections. As a potent immunosuppressor cell population, MDSCs can inhibit specific and non-specific immune responses via different mechanisms that, in turn, lead to disease persistence. One such mechanism by which MDSCs can activate their immunosuppressive effects is accomplished by secreting copious amounts of immunosuppressant molecules such as interleukin-10 (IL-10). In this article, we will focus on the pathological role of MDSC expansion in chronic inflammatory conditions including cancer, sepsis/infection, autoimmunity, asthma and ageing, as well as some of the mechanisms by which MDSCs/IL-10 contribute to the disease progression in such conditions.

تكمن أهمية البحث في دراسة الجانب القيادي من خلال رؤية الاتحادات المركزية لقيادات اللجنة الاولمبية والبارالمبية ومقارنة النتائج التي تم التوصل اليها من خلال مقياس القيادة الذكية والذي يشمل على المجالات وهي (الذكاء الشخصية – ذكاء الشعوري – ذكاء العقلاني – ذكاء الروحي) وما تواجهه اللجنة الاولمبية والبارالمبية من متغيرات متعددة على المستوى الاداري مما يتطلب منها إيجاد قيادة فاعلة لتلافي الاخطاء او الازمات التي من الممكن ان يتلافاها القائد الذكي. لذا وضع الباحثان بعض الأسئلة الآتية: ما مدى امتلاك اللجنةالاولمبية و البارالمبية لقيادات ذكية تحمل مؤهلات القيادة, ما هي الذكاءات القيادية التي يحملها قادة اللجنة الاولمبية او البارالمبية ؟ هل قادة اللجنة الاولمبية والبارالمبية لديهم القدرة على تحسين انفسهم بحيث يعملون على الجمع بين انواع القيادة الذكية وبلورتها بشكل عملي يخدم الاتحادات والموظفين للارتقاء بالعمل الاداري وصنع القرار الرياضي . تم استخدام المنهج الوصفي بالاسلوب المسحي وبطريقة العلاقات الارتباطية والمقارنة وتم اختيار عينة البحث من اعضاء الاتحادات المركزية للجنة الاولمبية والبارالمبية بواقع (50) عضوا لكل لجنة , حيث تم توزيع (100) استمارة اي بنسبة (50) استمارة لاتحادات اللجنة الاولمبية و(50) استمارة لاتحادات اللجنة البارالمبية , وقد اعتمد الباحثان على استبانه جاهزة لقياس متغيرات القيادة الذكية التي تم الحصول عليها من دراسة (علي عبد اللطيف علي 2019), وتم عرض الوصف الأحصائي لبيانات مقياسي القيادة الذكية للجنة الاولمبية والبارالمبية ومناقشتها فضلا عن عرض نتائج الفروق بين الاولمبية والبارلمبية في مقياس القيادة الذكية ومناقشتها, واستنتج الباحثان أن اعضاء الاتحادات المركزية البارالمبية التي تمثل عينة البحث تتمتع ببعض الخصائص القيادية لتحقيق الأهداف المطلوبة منها إلا أن السياسات التي تتبعها اللجنة البارالمبية قد أبعدتهم عن ممارسة دورهم القيادي أو مشاركتهم الفعلية في اتخاذ القرارات واكتفت بدورها في الاتحادات مما انعكس ذلك على أن يكون دورهم سلبياً أكثر مما يكون ايجابياً في حدوث أزمة. واوصى الباحثان العمل على تطوير المهارات للقيادة العليا ، وتعزيز ما تمتلكه من مهارات قيادية عن طريق تحسين قدراتهم ومهاراتهم في مجال الذكاء الشعوري والذكاء العقلاني والذكاء الروحي. وأن تساهم اللجنةالاولمبية والبارالمبية في زج اعضاء الاتحادات الخاصين في دورات القيادة لتكون لديهم المعرفة بالقيادة الإدارية ( وخاصة القيادة الذكية)، إدارة الأزمات، نظريات القيادة، المسؤولية الاجتماعية، نظم التحفيز، حيث لمس الباحثان أن القيادات الإدارية التي شملها البحث لديهم خبرة فنية في مجال عملهم دون الثقافة الإدارية الكافية.

Introduction Disaster zone medical relief has been criticised for poor quality care, lack of standardisation and accountability. Traditional patient safety practices of emergency medical teams (EMTs) in disaster zones were not well understood. Improving the quality of healthcare in disaster zones has gained importance within global health policy. Ascertaining patient safety practices of EMTs in disaster zones may identify areas of practice that can be improved.Methods A systematic search of OvidSP, Embase and Medline databases; key journals of interest; key grey literature texts; the databases of the WHO, Médecins Sans Frontieres and the International Committee of the Red Cross; and Google Scholar was performed. Descriptive studies, case reports, case series, prospective trials and opinion pieces were included with no limitation on date or language of publication.Results There were 9685 records, evenly distributed between the peer-reviewed and grey literature. Of these, 30 studies and 9 grey literature texts met the inclusion criteria and underwent qualitative synthesis. From these articles, 302 patient safety statements were extracted. Thematic analysis categorised these statements into 84 themes (total frequency 632). The most frequent themes were limb injury (9%), medical records (5.4%), surgery decision-making (4.6%), medicines safety (4.4%) and protocol (4.4%).Conclusion Patient safety practices of EMTs in disaster zones are weighted toward acute clinical care, particularly surgery. The management of non-communicable disease is under-represented. There is widespread recognition of the need to improve medical record-keeping. High-quality data and institutional level patient safety practices are lacking. There is no consensus on disaster zone-specific performance indicators. These deficiencies represent opportunities to improve patient safety in disaster zones.

The learning process for multilayered neural networks with many nodes makes heavy demands on computational resources. In some neural network models, the learning formulas, such as the Widrow–Hoff formula, do not change the eigenvectors of the weight matrix while flatting the eigenvalues. In infinity, these iterative formulas result in terms formed by the principal components of the weight matrix, namely, the eigenvectors corresponding to the non-zero eigenvalues. In quantum computing, the phase estimation algorithm is known to provide speedups over the conventional algorithms for the eigenvalue-related problems. Combining the quantum amplitude amplification with the phase estimation algorithm, a quantum implementation model for artificial neural networks using the Widrow–Hoff learning rule is presented. The complexity of the model is found to be linear in the size of the weight matrix. This provides a quadratic improvement over the classical algorithms. Quanta 2018; 7: 7–18.

Sulfur mustard (SM), a vesicating agent first used during World War I, remains a potent threat as a chemical weapon to cause intentional/accidental chemical emergencies. Eyes are extremely susceptible to SM toxicity. Nitrogen mustard (NM), a bifunctional alkylating agent and potent analog of SM, is used in laboratories to study mustard vesicant-induced ocular toxicity. Previously, we showed that SM-/NM-induced injuries (in vivo and ex vivo rabbit corneas) are reversed upon treatment with dexamethasone (DEX), a US Food and Drug Administration-approved, steroidal anti-inflammatory drug. Here, we optimized NM injuries in ex vivo human corneas and assessed DEX efficacy. For injury optimization, one cornea (randomly selected from paired eyes) was exposed to NM: 100 nmoles for 2 hours or 4 hours, and 200 nmoles for 2 hours, and the other cornea served as a control. Injuries were assessed 24 hours post NM-exposure. NM 100 nmoles exposure for 2 hours was found to cause optimal corneal injury (epithelial thinning [∼69%]; epithelial-stromal separation [6-fold increase]). In protein arrays studies, 24 proteins displayed ≥40% change in their expression in NM exposed corneas compared with controls. DEX administration initiated 2 hours post NM exposure and every 8 hours thereafter until 24 hours post-exposure reversed NM-induced corneal epithelial-stromal separation [2-fold decrease]). Of the 24 proteins dysregulated upon NM exposure, six proteins (delta-like canonical Notch ligand 1, FGFbasic, CD54, CCL7, endostatin, receptor tyrosine-protein kinase erbB-4) associated with angiogenesis, immune/inflammatory responses, and cell differentiation/proliferation, showed significant reversal upon DEX treatment (Student's t test; P ≤ 0.05). Complementing our animal model studies, DEX was shown to mitigate vesicant-induced toxicities in ex vivo human corneas. SIGNIFICANCE STATEMENT: Nitrogen mustard (NM) exposure-induced injuries were optimized in an ex vivo human cornea culture model and studies were carried out at 24 h post 100 nmoles NM exposure. Dexamethasone (DEX) administration (started 2 h post NM exposure and every 8 h thereafter) reversed NM-induced corneal injuries. Molecular mediators of DEX action were associated with angiogenesis, immune/inflammatory responses, and cell differentiation/proliferation, indicating DEX aids wound healing via reversing vesicant-induced neovascularization (delta-like canonical Notch ligand 1 and FGF basic) and leukocyte infiltration (CD54 and CCL7)., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Age-related macular degeneration (AMD) is a leading cause of blindness, and elucidating its underlying disease mechanisms is vital to the development of appropriate therapeutics. We identified differentially expressed genes (DEGs) and differentially spliced genes (DSGs) across the clinical stages of AMD in disease-affected tissue, the macular retina pigment epithelium (RPE)/choroid and the macular neural retina within the same eye. We utilized 27 deeply phenotyped donor eyes (recovered within a 6 h postmortem interval time) from Caucasian donors (60-94 years) using a standardized published protocol. Significant findings were then validated in an independent set of well-characterized donor eyes ( n = 85). There was limited overlap between DEGs and DSGs, suggesting distinct mechanisms at play in AMD pathophysiology. A greater number of previously reported AMD loci overlapped with DSGs compared to DEGs between disease states, and no DEG overlap with previously reported loci was found in the macular retina between disease states. Additionally, we explored allele-specific expression (ASE) in coding regions of previously reported AMD risk loci, uncovering a significant imbalance in C3 rs2230199 and CFH rs1061170 in the macular RPE/choroid for normal eyes and intermediate AMD (iAMD), and for CFH rs1061147 in the macular RPE/choroid for normal eyes and iAMD, and separately neovascular AMD (NEO). Only significant DEGs/DSGs from the macular RPE/choroid were found to overlap between disease states. STAT1 , validated between the iAMD vs. normal comparison, and AGTPBP1 , BBS5 , CERKL , FGFBP2 , KIFC3 , RORα , and ZNF292 , validated between the NEO vs. normal comparison, revealed an intricate regulatory network with transcription factors and miRNAs identifying potential upstream and downstream regulators. Findings regarding the complement genes C3 and CFH suggest that coding variants at these loci may influence AMD development via an imbalance of gene expression in a tissue-specific manner. Our study provides crucial insights into the multifaceted genomic underpinnings of AMD (i.e., tissue-specific gene expression changes, potential splice variation, and allelic imbalance), which may open new avenues for AMD diagnostics and therapies specific to iAMD and NEO.

Nitrogen mustard (NM) is an analogue of the potent vesicating agent sulfur mustard, with well-established ocular injury models in rabbit eyes to study vesicant-induced ocular toxicity. The effects of NM-exposure to eyes may include irritation, redness, inflammation, fibrosis, epithelial degradation, blurred vision, partial/complete blindness, which may be temporary or permanent, depending on the route, duration, and dosage of exposure. Effective countermeasures against vesicant exposure are presently not available and are warranted in case of any terrorist activity or accidental leakage from stockpiles. Herein, our focus was to evaluate whether dexamethasone (DEX), an FDA approved potent corticosteroid with documented anti-inflammatory activities, could be an effective treatment modality. Accordingly, utilizing NM-induced corneal injuries in rabbit ocular in vivo model, we examined and compared the efficacy of DEX treatments when administration was started at early (2 h), intermediate (4 h), and late (6 h) therapeutic windows of intervention after NM-exposure and administered every 8 h thereafter. The effects of NM-exposure and DEX treatments were evaluated on clinical (corneal opacity, ulceration, and neovascularization), biological (epithelial thickness, epithelial-stromal separation, blood vessels density, and inflammatory cell and keratocyte counts) and molecular (COX-2 and VEGF expression) parameters, at day 1, 3, 7 and 14. Results indicated that DEX treatment markedly and effectively reversed the NM-induced injury markers in rabbit corneas. Early administration of DEX at 2 h was found to be most effective in reversing NM-induced corneal injuries, followed by DEX 4 h and DEX 6 h administration initiation, indicating that DEX has best efficacy at the early therapeutic window in our study model., (Copyright © 2022 Elsevier Inc. All rights reserved.)

With a possibility for the use of chemical weapons in battlefield or in terrorist activities, effective therapies against the devastating ocular injuries, from their exposure, are needed. Oxygen plays a vital role in ocular tissue preservation and wound repair. We tested the efficacy of supersaturated oxygen emulsion (SSOE) in reducing ex vivo corneal and keratocyte injury from chloropicrin (CP). CP, currently used as a pesticide, is a chemical threat agent like the vesicating mustard agents and causes severe corneal injury. Since our previous study in human corneal epithelial cells showed the treatment potential of SSOE (55 %), we further tested its efficacy in an ex vivo CP-induced rabbit corneal injury model. Corneas were exposed to CP (700 nmol) for 2 h, washed and cultured with or without SSOE for 24 h or 96 h. At 96 h post CP exposure, SSOE treatment presented a healing tendency of the corneal epithelial layer, and abrogated the CP-induced epithelial apoptotic cell death. SSOE treatment also reduced the CP induced DNA damage (H2A.X phosphorylation) and inflammatory markers (e.g. MMP9, IL-21, MIP-1β, TNFα). Further examination of the treatment efficacy of SSOE alone or in combination with other therapies in in vivo cornea injury models for CP and vesicants, is warranted., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, has been implicated in the onset and development of the ocular complications of diabetes, including cataracts and retinopathy. Despite decades of research conducted to address possible mechanisms, questions still persist in understanding if or how AR contributes to imbalances leading to diabetic eye disease. To address these questions, we created a strain of transgenic mice engineered for the overexpression of human AR (AR-Tg). In the course of monitoring these animals for age-related retinal phenotypes, we observed signs of Müller cell gliosis characterized by strong immunostaining for glial fibrillary acidic protein. In addition, we observed increased staining for Iba1, consistent with an increase in the number of retinal microglia, a marker of retinal inflammation. Compared to age-matched nontransgenic controls, AR-Tg mice showed an age-dependent loss of Brn3a-positive retinal ganglion cells and an associated decrease in PERG amplitude. Both RGC-related phenotypes were rescued in animals treated with Sorbinil in drinking water. These results support the hypothesis that increased levels of AR may be a risk factor for structural and functional changes known to accompany retinopathy in humans.

Objective: To demonstrate the existence of lymphatics in the canine anterior uvea using lymphatic-specific markers Lyve-1, Prox-1, and podoplanin, the endothelial cell marker CD31, and basement membrane matrix marker collagen IV., Design: Prospective Study., Animals: Eight normal globes from animals euthanized for unrelated health problems., Procedures: Sagittally cut serial sections of six normal canine eyes were immunofluorescence double-stained with Lyve-1 and CD31 and single-stained with colorimetric Prox-1 and collagen IV. Three serial sections from 2 additional eyes were cut in the coronal plane at the level of the ciliary body and immunofluorescence double-stained with Lyve-1 and CD31 to map lymphatic channel distribution. Lymphatics from normal canine lymph nodes were used for validation of podoplanin., Results: Four of 6 of the sagitally sectioned eyes had Lyve-1-positive lymphatic-like structures that were distinct from CD31-positive blood vessels in the iris base and ciliary body. Both of the coronally sectioned globes had Lyve-1-positive lymphatic-like structures in the ciliary body. The location of these structures was evaluated and found to be diffusely present circumferentially around the ciliary body., Conclusion and Clinical Relevance: These results support the existence of lymphatic channels in the anterior uveal tract of the canine eye. This could indicate the presence of a novel uveolymphatic outflow pathway, which may play a role in aqueous humor outflow. Future studies are needed to confirm the existence and elucidate the role of this proposed uveolymphatic outflow pathway and potentially develop novel treatment options for managing glaucoma., (© 2021 American College of Veterinary Ophthalmologists.)

Purpose: To quantify the effects of modified Ahmed glaucoma valves ® (AGV) with anti-fibrotic plate coatings or a plate surface micro-pattern on outflow resistance and tissue response., Methods: Twelve New Zealand rabbits were divided into four groups: commercially available AGV implants (n = 3), AGV with hydrophilic coating (n = 3), AGV with heparin coating (n = 3), and AGV with a plate surface micro-pattern (n = 3). After 6 weeks, the anterior chamber silicone tube was cannulated in situ and perfused with 2.5 μL/min of saline. The pressures were recorded with a perfusion system to measure outflow resistance. The rabbits were then euthanized followed by enucleation of all eyes for bleb histological analyses., Results: Hydrostatic pressures were significantly lower in AGVs with the hydrophilic plate coating (mean difference -9.6 mm Hg; p < 0.001), heparin-coated plates (mean difference -4.4 mm Hg; p < 0.001), and micro-patterned plates (mean difference -18.6 mm Hg, p < 0.001), indicating lower outflow resistance compared to control AGV models. Fibrotic encapsulation was lower in hydrophilic plate coating (84.2 μm; mean difference -6.2 μm, p = 0.425), micro-patterned surface (63.7 μm; mean difference -26.7 μm, p = 0.003), and heparin plate coating (49.3 μm; mean difference -41.1 μm, p = 0.006) when compared to control AGV models., Conclusions: Modified AGVs with plate coatings and AGVs with micro-patterned plates both appear to reduce postoperative fibrotic encapsulation and aqueous outflow resistance by altering the tissue response to implanted materials. Further studies are needed to characterize the safety and role of plate surface modifications on glaucoma drainage devices.

Chloropicrin (CP), a warfare agent now majorly used as a soil pesticide, is a strong irritating and lacrimating compound with devastating toxic effects. To elucidate the mechanism of its ocular toxicity, toxic effects of CP (0-100 μM) were studied in primary human corneal epithelial (HCE) cells. CP exposure resulted in reduced HCE cell viability and increased apoptotic cell death with an up-regulation of cleaved caspase-3 and poly ADP ribose polymerase indicating their contribution in CP-induced apoptotic cell death. Following CP exposure, cells exhibited increased expression of heme oxygenase-1, and phosphorylation of H2A.X and p53 as well as 4-hydroxynonenal adduct formation, suggesting oxidative stress, DNA damage and lipid peroxidation. CP also caused increases in mitogen activated protein kinase-c-Jun N-terminal kinase and inflammatory mediator cyclooxygenase-2. Proteomic analysis revealed an increase in the carbonylation of 179 proteins and enrichment of pathways (including proteasome pathway and catabolic process) in HCE cells following CP exposure. CP-induced oxidative stress and lipid peroxidation can enhance protein carbonylation, prompting alterations in corneal epithelial proteins as well as perturbing signaling pathways resulting in toxic effects. Pathways and major processes identified following CP exposure could be lead-hit targets for further biochemical and molecular characterization as well as therapeutic intervention., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019. Published by Elsevier B.V.)

Sulfur mustard (SM), a potent vesicating chemical warfare agent, and its analog nitrogen mustard (NM), are both strong bi-functional alkylating agents. Eyes, skin, and the respiratory system are the main targets of SM and NM exposure; however, ocular tissue is most sensitive, resulting in severe ocular injury. The mechanism of ocular injury from vesicating agents' exposure is not completely understood. To understand the injury mechanism from exposure to vesicating agents, NM has been previously employed in our toxicity studies on primary human corneal epithelial cells and ex vivo rabbit cornea organ culture model. In the current study, corneal toxicity from NM ocular exposure (1%) was analyzed for up to 28 days post-exposure in New Zealand White male rabbits to develop an acute corneal injury model. NM exposure led to conjunctival and eyelid swelling within a few hours after exposure, in addition to significant corneal opacity and ulceration. An increase in total corneal thickness and epithelial degradation was observed starting at day 3 post-NM exposure, which was maximal at day 14 post-exposure and did not resolve until 28 days post-exposure. There was an NM-induced increase in the number of blood vessels and inflammatory cells, and a decrease in keratocytes in the corneal stroma. NM exposure resulted in increased expression levels of cyclooxygenase-2, Interleukin-8, vascular endothelial growth factor and Matrix Metalloproteinase 9 indicating their involvement in NM-induced corneal injury. These clinical, biological, and molecular markers could be useful for the evaluation of acute corneal injury and to screen for therapies against NM- and SM-induced ocular injury., (Copyright © 2019 Elsevier Inc. All rights reserved.)

To compare the histological effects of trans-scleral cyclophotocoagulation (TCP) performed with two different probes, the G-probe (IRIDEX Medical Instruments, Mountain View, CA, USA) and the Ciliprobe (Katalyst Surgical, Chesterfield, MO, USA). TCP was performed on two human cadaver eyes from the same corpse. The vertical meridian was marked and opposite sides were treated using either the G-probe or Ciliprobe. The first eye was treated with each probe at 2000ms/2000 mW and the second eye at 3000ms/1500 mW. Histological examination revealed separation and loss of the non-pigmented ciliary epithelium as well as vacuolization in all sections for both probes and settings. Changes to the non-pigmented ciliary epithelium treated at 3000ms/1500 mW were similar between the two probes. A slightly more complete separation of the non-pigmented epithelium was noted on the Ciliprobe treated sections as compared to the G-probe treated sections in the eye treated at 2000ms/2000 mW. Therefore, in human cadaver eyes, both the G-probe and Ciliprobe produced separation, vacuolization, and loss of the non-pigmented ciliary epithelium at two different, clinically utilized settings.

In general, neurons belonging to the central nervous system (CNS), such as retinal ganglion cells (RGCs), do not regenerate. Due to this, strategies have emerged aimed at protecting and regenerating these cells. Neurotrophic factor (NTF) supplementation has been a promising approach but is limited by length of delivery and delivery vehicle. For this study, we tested a polymeric delivery system (sulfonated reverse thermal gel or SRTG) engineered to deliver cilliary neurotrophic factor (CNTF), while also being injectable. A rat optic nerve crush (ONC) model was used to determine the neuroprotective and regenerative capacity of our system. The results demonstrate that one single intravitreal injection of SRTG-CNTF following ONC showed significant protection of RGC survival at both 1 and 2 week time points, when compared to the control groups. Furthermore, there was no significant difference in the RGC count between the eyes that received the SRTG-CNTF following ONC and a healthy control eye. Intravitreal injection of the polymer system also induced noticeable axon regeneration 500 μ m downstream from the lesion site compared to all other control groups. There was a significant increase in Müller cell response in groups that received the SRTG-CNTF injection following optic nerve crush also indicative of a regenerative response. Finally, higher concentrations of CNTF released from SRTG-CNTF showed a protective effect on RGCs and Müller cell response at a longer time point (4 weeks). In conclusion, we were able to show a neuroprotective and regenerative effect of this polymer SRTG-CNTF delivery system and the viability for treatment of neurodegenerations., Competing Interests: The authors declare no competing financial interest.

Purpose: Cataract surgery is a procedure by which the lens fiber cell mass is removed from its capsular bag and replaced with a synthetic intraocular lens. Postoperatively, remnant lens epithelial cells can undergo an aberrant wound healing response characterized by an epithelial-to-mesenchymal transition (EMT), leading to posterior capsular opacification (PCO). Aldose reductase (AR) inhibition has been shown to decrease EMT markers in cell culture models. In this study, we aim to demonstrate that AR inhibition can attenuate induction of EMT markers in an in vivo model of cataract surgery., Methods: A modified extracapsular lens extraction (ECLE) was performed on C57BL/6 wildtype, AR overexpression (AR-Tg), and AR knockout mice. Immunofluorescent staining for the myofibroblast marker α-smooth muscle actin (α-SMA), epithelial marker E-cadherin, and lens fiber cell markers αA-crystallin and Aquaporin 0 was used to characterize postoperative PCO. Quantitative reverse transcription PCR (qRT-PCR) was employed to quantify postoperative changes in α-SMA, vimentin, fibronectin, and E-cadherin. In a separate experiment, the AR inhibitor Sorbinil was applied postoperatively and qRT-PCR was used to assess changes in EMT markers., Results: Genetic AR knockout reduced ECLE-induced upregulation of α-SMA and downregulation of E-cadherin. These immunofluorescent changes were mirrored quantitatively in changes in mRNA levels. Similarly, Sorbinil blocked characteristic postoperative EMT changes in AR-Tg mice. Interestingly, genetic AR knockout did not prevent postoperative induction of the lens fiber cell markers αA-crystallin and Aquaporin 0., Conclusions: AR inhibition prevents the postoperative changes in EMT markers characteristic of PCO yet preserves the postoperative induction of lens fiber cell markers.

Purpose: The purpose of this article was to evaluate how human trabecular meshwork (TM) is influenced by the chronic presence of trabecular bypass implants., Methods: Human TM samples were obtained intraoperatively from 3 patients who had previously undergone implantation of a trabecular micro-bypass stent. Trabecular strips were obtained with a goniotomy blade from areas directly adjacent to the stent after stent removal. Tissue samples were preserved, processed, cut, and stained according to standardized laboratory protocol. Harvested samples were compared with human cadaveric TM from an eye without ocular disease as well as TM obtained from a glaucomatous eye without prior stent placement., Results: In all samples, a significant increase in the amount of fibrous material compared with cellular material was noted when compared with controls. In a single strip, a basement membrane-like structure was noted, which correlated with a semiopaque membrane noted intraoperatively overlying the stent and adjacent TM. Further, TM cells were absent from areas adjacent to the stent implantation site with related collapse of collagen beams., Conclusions: These findings indicate that inflammatory and fibrotic changes are present surrounding the device with clear differences noted when compared with both healthy and glaucomatous controls. These changes suggest a possible etiology for device failure over time. Further studies are necessary to tease out differences in TM tissue reaction to various implant materials as well as to make comparisons to procedures that excise TM.

Lewisite (LEW), a potent arsenical vesicating chemical warfare agent, poses a continuous risk of accidental exposure in addition to its feared use as a terrorist weapon. Ocular tissue is exquisitely sensitive to LEW and exposure can cause devastating corneal lesions. However, detailed pathogenesis of corneal injury and related mechanisms from LEW exposure that could help identify targeted therapies are not available. Using an established consistent and efficient exposure system, we evaluated the pathophysiology of the corneal injury in New Zealand white rabbits following LEW vapor exposure (at 0.2 mg/L dose) for 2.5 and 7.5 min, for up to 28 day post-exposure. LEW led to an increase in total corneal thickness starting at day 1 post-exposure and epithelial degradation starting at day 3 post-exposure, with maximal effect at day 7 postexposure followed by recovery at later time points. LEW also led to an increase in the number of blood vessels and inflammatory cells but a decrease in keratocytes with optimal effects at day 7 postexposure. A significant increase in epithelial-stromal separation was observed at days 7 and 14 post 7.5 min LEW exposure. LEW also caused an increase in the expression levels of cyclooxygenase-2, IL-8, vascular endothelial growth factor, and matrix metalloproteinase-9 at all the study time points indicating their involvement in LEW-induced inflammation, vesication, and neovascularization. The outcomes here provide valuable LEW-induced corneal injury endpoints at both lower and higher exposure durations in a relevant model system, which will be helpful to identify and screen therapies against LEW-induced corneal injury., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Ocular injury by lewisite (LEW), a potential chemical warfare and terrorist agent, results in edema of eyelids, inflammation, massive corneal necrosis and blindness. To enable screening of effective therapeutics to treat ocular injury from LEW, useful clinically-relevant endpoints are essential. Hence, we designed an efficient exposure system capable of exposing up to six New-Zealand white rabbits at one time, and assessed LEW vapor-induced progression of clinical ocular lesions mainly in the cornea. The right eye of each rabbit was exposed to LEW (0.2 mg/L) vapor for 2.5, 5.0, 7.5 and 10.0 min and clinical progression of injury was observed for 28 days post-exposure (dose-response study), or exposed to same LEW dose for 2.5 and 7.5 min and clinical progression of injury was observed for up to 56 days post-exposure (time-response study); left eye served as an unexposed control. Increasing LEW exposure caused corneal opacity within 6 h post-exposure, which increased up to 3 days, slightly reduced thereafter till 3 weeks, and again increased thereafter. LEW-induced corneal ulceration peaked at 1 day post-exposure and its increase thereafter was observed in phases. LEW exposure induced neovascularization starting at 7 days which peaked at 22-35 days post-exposure, and remained persistent thereafter. In addition, LEW exposure caused corneal thickness, iris redness, and redness and swelling of the conjunctiva. Together, these findings provide clinical sequelae of ocular injury following LEW exposure and for the first time establish clinically-relevant quantitative endpoints, to enable the further identification of histopathological and molecular events involved in LEW-induced ocular injury.

Sensory-somatic nervous system neurons, such as retinal ganglion cells (RGCs), are typically thought to be incapable of regenerating. However, it is now known that these cells may be stimulated to regenerate by providing them with a growth permissive environment. We have engineered an injectable microenvironment designed to provide growth-stimulating cues for RGC culture. Upon gelation, this injectable material not only self-assembles into laminar sheets, similar to retinal organization, but also possesses a storage modulus comparable to that of retinal tissue. Primary rat RGCs were grown, stained, and imaged in this three-dimensional scaffold. We were able to show that RGCs grown in this retina-like structure exhibited characteristic long, prominent axons. In addition, RGCs showed a consistent increase in average axon length and neurite-bearing ratio over the 7 day culture period, indicating this scaffold is capable of supporting substantial RGC axon extension.

Purpose: To visualize and quantify the three-dimensional (3D) spatial relationships of the structures of the aqueous outflow system (AOS) within intact enucleated mouse eyes using spectral two-photon microscopy (TPM) techniques., Methods: Spectral TPM, including two-photon autofluorescence (TPAF) and second-harmonic generation (SHG), were used to image the small structures of the AOS within the limbal region of freshly enucleated mouse eyes. Long infrared excitation wavelengths (930 nm) were used to reduce optical scattering and autofluorescent background. Image stacks were collected for 3D image rendering and structural segmentation. For anatomical reference, vascular perfusion with fluorescent-conjugated dextran (150 KDa) and trans-corneal perfusion with 0.1 μm fluorescent polystyrene beads were separately performed to identify the episcleral veins (EV) and the trabecular meshwork (TM) and Schlemm's canal (SC), respectively., Results: Three-dimensional rendering and segmentation of spectral two-photon images revealed detailed structures of the AOS, including SC, collector channels (CC), and aqueous veins (AV). The collagen of the TM was detected proximal to SC. The long and short axes of the SC were 82.2 ± 22.2 μm and 6.7 ± 1.4 μm. The diameters of the CC averaged 25.6 ± 7.9 μm where they originated from the SC (ostia), enlarged to 34.1 ± 13.1 μm at the midpoint, and narrowed to 18.3 ± 4.8 μm at the junction of the AV. The diameter of the AV averaged 12.5 ± 3.4 μm., Conclusions: Spectral TPM can be used to reconstruct and measure the spatial relationships of both large and small AOS structures, which will allow for better understanding of distal aqueous outflow dynamics.

Purpose: To evaluate the toxic effects and associated mechanisms in corneal tissue exposed to the vesicating agent, nitrogen mustard (NM), a bifunctional alkylating analog of the chemical warfare agent sulfur mustard., Methods: Toxic effects and associated mechanisms were examined in maximally affected corneal tissue using corneal cultures and human corneal epithelial (HCE) cells exposed to NM., Results: Analysis of ex vivo rabbit corneas showed that NM exposure increased apoptotic cell death, epithelial thickness, epithelial-stromal separation, and levels of vascular endothelial growth factor, cyclooxygenase 2, and matrix metalloproteinase-9. In HCE cells, NM exposure resulted in a dose-dependent decrease in cell viability and proliferation, which was associated with DNA damage in terms of an increase in p53 ser15, total p53, and H2A.X ser139 levels. NM exposure also induced caspase-3 and poly ADP ribose polymerase cleavage, suggesting their involvement in NM-induced apoptotic death in the rabbit cornea and HCE cells. Similar to rabbit cornea, NM exposure caused an increase in cyclooxygenase 2, matrix metalloproteinase-9, and vascular endothelial growth factor levels in HCE cells, indicating a role of these molecules and related pathways in NM-induced corneal inflammation, epithelial-stromal separation, and neovascularization. NM exposure also induced activation of activator protein 1 transcription factor proteins and upstream signaling pathways including mitogen-activated protein kinases and Akt protein kinase, suggesting that these could be key factors involved in NM-induced corneal injury., Conclusions: Results from this study provide insight into the molecular targets and pathways that could be involved in NM-induced corneal injuries laying the background for further investigation of these pathways in vesicant-induced ocular injuries, which could be helpful in the development of targeted therapies.

Background: The findings that α-crystallins are multi-functional proteins with diverse biological functions have generated considerable interest in understanding their role in health and disease. Recent studies have shown that chaperone peptides of α-crystallin could be delivered into cultured cells and in experimental animals with beneficial effects against protein aggregation, oxidation, inflammation and apoptosis., Scope of Review: In this review, we will summarize the latest developments on the therapeutic potential of α-crystallins and their functional peptides., Major Conclusions: α-Crystallins and their functional peptides have shown significant favorable effects against several diseases. Their targeted delivery to tissues would be of great therapeutic benefit. However, α-crystallins can also function as disease-causing proteins. These seemingly contradictory functions must be carefully considered prior to their therapeutic use., General Significance: αA and αB-Crystallin are members of the small heat shock protein family. These proteins exhibit molecular chaperone and anti-apoptotic activities. The core crystallin domain within these proteins is largely responsible for these prosperities. Recent studies have identified peptides within the crystallin domain of both α- and αB-crystallins with remarkable chaperone and anti-apoptotic activities. Administration of α-crystallin or their functional peptides has shown substantial inhibition of pathologies in several diseases. However, α-crystallins have been shown to promote disease-causing pathways. These two sides of the proteins are discussed in this review. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Misfolded protein aggregation, including cataract, cause a significant amount of blindness worldwide. α-Crystallin is reported to bind misfolded proteins and prevent their aggregation. We hypothesize that supplementing retina and lens with α-crystallin may help to delay disease onset. The purpose of this study was to determine if αB-crystallin subunits containing a cell penetration peptide (gC-tagged αB-crystallin) facilitate the uptake of wild type αA-crystallin (WT-αA) in lens and retina. Recombinant human αB-crystallin was modified by the addition of a novel cell penetration peptide derived from the gC gene product of herpes simplex virus (gC-αB). Recombinant gC-αB and wild-type αA-crystallin (WT-αA) were purified from E. coli over-expression cultures. After Alexa-labeling of WT-αA, these proteins were mixed at ratios of 1:2, 1:5 and 1:10, respectively, and incubated at 37°C for 4 hours to allow for subunit exchange. Mixed oligomers were subsequently incubated with tissue culture cells or mouse organ cultures. Similarly, crystallin mixtures were injected into the vitreous of rat eyes. At various times after exposure, tissues were harvested and analyzed for protein uptake by confocal microscopy or flow cytometry. Chaperone-like activity assays were performed on α-crystallins ratios showing optimal uptake using chemically-induced or heat induced substrate aggregation assays. As determined by flow cytometry, a ratio of 1:5 for gC-αB to WT-αA was found to be optimal for uptake into retinal pigmented epithelial cells (ARPE-19). Chaperone-like activity assays demonstrated that hetero-oligomeric complex of gC-αB to WT-αA (in 1:5 ratio) retained protein aggregation protection. We observed a significant increase in protein uptake when optimized (gC-αB to WT-αA (1:5 ratio)) hetero-oligomers were used in mouse lens and retinal organ cultures. Increased levels of α-crystallin were found in lens and retina following intravitreal injection of homo- and hetero-oligomers in rats.

Purpose: To demonstrate lipid-specific imaging of the retina through the use of third harmonic generation (THG), a multiphoton microscopic technique in which tissue contrast is generated from optical inhomogeneities., Methods: A custom fiber laser and multiphoton microscope was constructed and optimized for simultaneous two-photon autofluorescence (TPAF) and THG retinal imaging. Imaging was performed using fixed-frozen sections of mouse eyes without the use of exogenous fluorescent dyes. In parallel experiments, a fluorescent nuclear stain was used to verify the location of the retinal cell nuclei., Results: Simultaneous THG and TPAF images revealed all retinal layers with subcellular resolution. In BALB/c strains, the THG signal stems from the lipidic organelles of the cellular and nuclear membranes. In the C57BL/6 strain, the THG signal from the RPE cells originates from the pigmented granules., Conclusions: THG microscopy can be used to image structures of the mouse retina using contrast inherent to the tissue and without the use of a fluorescent dye or exogenously expressed recombinant protein.

Purpose. To compare morphologic changes in human trabecular meshwork (TM) after selective laser trabeculoplasty (SLT) and argon laser trabeculoplasty (ALT). Design. Laboratory evaluation of ex vivo human eye TM after laser trabeculoplasty. Methods. Corneoscleral rims from human cadaver eyes were sectioned and treated with varying powers of either SLT or ALT. Specimens were examined using light microscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Results. TEM of SLT at all powers resulted in disrupted TM cells with cracked and extracellular pigment granules. SEM of SLT samples treated at high power revealed tissue destruction with scrolling of trabecular beams. SEM of ALT-treated tissue showed increasing destruction with exposure to higher power. The presence or absence of "champagne" bubbles during SLT did not alter the histologic findings. Conclusions. SLT-treated human TM revealed disruption of TM cells with cracked, extracellular pigment granules, particularly at higher treatment powers. Tissue scrolling was noted at very high SLT energy levels. ALT-treated tissue showed significant damage to both the superficial and deeper TM tissues in a dose-dependent fashion. Further studies are needed to guide titration of treatment power to maximize the IOP-lowering effect while minimizing both energy delivered and damage to target tissues.

In addition to their key role as structural lens proteins, α-crystallins also appear to confer protection against many eye diseases, including cataract, retinitis pigmentosa, and macular degeneration. Exogenous recombinant α-crystallin proteins were examined for their ability to prevent cell death induced by heat or oxidative stress in a human lens epithelial cell line (HLE-B3). Wild type αA- or αB-crystallin (WT-αA and WT-αB) and αA- or αB-crystallins, modified by the addition of a cell penetration peptide (CPP) designed to enhance the uptake of proteins into cells (gC-αB, TAT-αB, gC-αA), were produced by recombinant methods. In vitro chaperone-like assays were used to assay the ability of α-crystallins to protect client proteins from chemical or heat induced aggregation. In vivo viability assays were performed in HLE-B3 to determine whether pre-treatment with α-crystallins reduced death after exposure to oxidative or heat stress. Most of the five recombinant α-crystallin proteins tested conferred some in vitro protection from protein aggregation, with the greatest effect seen with WT-αB and gC-αB. All α-crystallins displayed significant protection to oxidative stress induced cell death, while only the αB-crystallins reduced cell death induced by thermal stress. Our findings indicate that the addition of the gC tag enhanced the protective effect of αB-crystallin against oxidative but not thermally-induced cell death. In conclusion, modifications that increase the uptake of α-crystallin proteins into cells, without destroying their chaperone-like activity and anti-apoptotic functions, create the potential to use these proteins therapeutically., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Purpose: The aim of this study was to nondestructively monitor morphological changes to the lipid membranes of primary cultures of living human trabecular meshwork cells (hTMC) without the application of exogenous label., Methods: Live hTMC were imaged using two nonlinear optical techniques: coherent anti-Stokes Raman scattering (CARS) and two-photon autofluorescence (TPAF). The hTMC were treated with a commercial formulation of latanoprost (0.5 μg/mL) for 24 hours before imaging. Untreated cells and cells treated with vehicle containing the preservative benzalkonium chloride (BAK; 2 μg/mL) were imaged as controls. After CARS/TPAF imaging, hTMC were fixed, stained with the fluorescent lipid dye Nile Red, and imaged by conventional confocal microscopy to verify lipid membrane structures., Results: Analysis of CARS/TPAF images of hTMC treated with latanoprost revealed multiple intracellular lipid membranes absent from untreated or BAK-treated hTMC. Treatment of hTMC with sodium fluoride or ouabain, agents shown to cause morphological changes to hTMC, also did not induce formation of intracellular lipid membranes., Conclusions: CARS microscopy detected changes in living hTMC morphology that were validated by subsequent histological stain. Prostaglandin-induced changes to hTMC involved rearrangement of lipid membranes within these cells. These in vitro results identify a novel biological response to a class of antiglaucoma drugs, and further experiments are needed to establish how this effect is involved in the hypotensive action of prostaglandin analogues in vivo.

Purpose: The aim of this study was to image the cellular and noncellular structures of the cornea and limbus in an intact mouse eye using the vibrational oscillation of the carbon-hydrogen bond in lipid membranes and autofluorescence as label-free contrast agents., Methods: Freshly enucleated mouse eyes were imaged using two nonlinear optical techniques: coherent anti-Stokes Raman scattering (CARS) and two-photon autofluorescence (TPAF). Sequential images were collected through the full thickness of the cornea and limbal regions. Line scans along the transverse/sagittal axes were also performed., Results: Analysis of multiple CARS/TPAF images revealed that corneal epithelial and endothelial cells could be identified by the lipid-rich plasma membrane CARS signal. The fluorescent signal from the collagen fibers of the corneal stroma was evident in the TPAF channel. The transition from the cornea to sclera at the limbus was marked by a change in collagen pattern (TPAF channel) and thickness of surface cells (CARS channel). Regions within the corneal stroma that lack collagen autofluorescence coincided with CARS signal, indicating the presence of stromal fibroblasts or nerve fibers., Conclusions: The CARS technique was successful in imaging cells in the intact mouse eye, both at the surface and within corneal tissue. Multiphoton images were comparable to histologic sections. The methods described here represent a new avenue for molecular specific imaging of the mouse eye. The lack of need for tissue fixation is unique compared with traditional histology imaging techniques.

Purpose: Oxidative stress plays a key role in the pathophysiology of glaucoma. This study was designed to assess ethyl pyruvate (EP) as a novel antioxidative agent in cultured human trabecular meshwork (hTM) cells., Methods: Primary hTM cells were cultured on collagen matrices. Tolerance to EP was assessed at various concentrations using fluorescent vital dyes (live/dead) and metabolic (1-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. After the candidate doses were identified, cells received either preincubation with EP before hydrogen peroxide stressing or pre- and coincubation with EP before and during stressing. Live/dead and metabolic activity assays were used to quantify oxidative damage., Results: Cultured hTM cells were well tolerant of EP concentrations at or below 10 mM while higher doses showed significant levels of cytotoxicity. In the peroxide stress assays, samples that received pre- and cotreatment with all concentrations of EP showed significantly increased cell survival and maintenance of metabolic activity. However, samples that received only pretreatment did not show a significant increase in survival rates and lost nearly all metabolic activity after peroxide-induced stressing., Conclusions: This work suggests that EP is a potent antioxidant that is well tolerated by hTM cells; however, EP's potential as a therapeutic agent for glaucoma is limited by its inability to enhance endogenous antioxidant capacity. A continuous drug delivery system may be needed to realize the full therapeutic potential of EP for treatment of glaucoma.