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It is difficult to dispute that nurses are the hardest working individuals within the healthcare industry today. They manage and provide patient care in quick-paced shifts that typically exceed twelve hours. Since these professionals work mainly on their feet, they require dependable nursing shoes to avert the development of foot disorders. Crocs are known to be exceptionally comfy and they provide a high degree of slip-resistance. If you are a newly qualified nurse, one question that may be on your mind now is: Can nurses wear crocs? This post will talk about everything you need to know regarding wearing crocs in healthcare facilities and hospitals.
See also: Best Crocs For Nurses
Crocs come with several features that make working many hours on feet less painful and tiring. For this reason, these shoes have been extremely popular among nurses and other hospital staff for several years. However, some hospitals have banned the use of these shoes due to specific issues. Some of these concerns are:
- Blood and other body fluids can seep in through the ventilation openings and result in severe infections
- Nurses and other medical workers can get poked by a contaminated needle that falls through the ventilation openings.
- Crocs with straps worn incorrectly can lead to severe accidents
Probably due to these concerns, the Crocs Company has developed a shoe line specifically for healthcare professionals including nurses. Many of the shoes in this line come with all the comfort attributes that make crocs so impressive: including Crocs Lock slip-resistant tread, a massaging footbed, easy to clean, and quick-drying. The interesting aspect is that many of these shoes do not have openings at the top.
Thus, returning to the question of whether nurses can wear Crocs, the answer is yes. Below are some of the crocs styles that are widely permitted for healthcare professionals in most parts of the globe.
- Crocs Men’s and Women’s Specialist II clog
- Croc’s Women’s Neria Pro II Clog
- Crocs Mercy clog
- Crocs Unisex – Adult On The Clock Clog
Table of Contents
Why Do Nurses Wear Crocs?
Nurses spend the majority of their workday standing and walking on concrete floors. Prolonged standing and walking at work can result in health problems like backache and leg cramps. Many of these problems can be averted by wearing comfortable work shoes. Made from Croslite, crocs are without a doubt among the coziest shoes for all-day standing and walking. Their flexible and plush insoles adhere to your foot’s natural outline, providing enhanced comfort and support. These shoes are excellent shock absorbers and help alleviate pain in the joints. They also allow for excellent ventilation so you will not have to bother about the buildup of sweat and moisture in the shoes.
Apart from providing superlative comfort, Crocs are also engineered to enhance walking. They provide arch support and ensure that your feet stay in a healthy, balanced position. Poor arch support can lead to misalignment of the entire body, causing back, knee, hip, pelvis, and pelvis problems. In contrast, shoes with excellent arch support can alleviate fatigue, help with balance, and even help ward off foot problems like plantar fasciitis. Crocs are engineered to keep your feet adequately aligned so can go about your duties pain-free.
See also: Best Shoes for Nurses with High Arches
Shoelaces are great because they help to deliver customizability as well as lock the foot in place preventing it from rubbing and moving around. However, they can sometimes get annoying particularly if you work mostly on your feet. For example, a loose lace can result in a fall when you are rushing to take care of an emergency.
The Crocs models permitted for nurses do not come with laces. Nurses love wearing these shoes because they allow them to move as fast as they want without having to bother about loose laces that might cause them to stumble. Besides, tying shoelaces requires time which might be in short supply within a fast-paced hospital environment.
Simple to clean
Crocs are crafted for simple clean-ups. They are made using waterproof and odor-resistant materials. Cleaning shoes made of fabric requires many steps of washing and scrubbing using dishwashing liquids. Removing dirt from a plain, even surface is a lot simpler. To clean a pair of Crocs nursing shoes, simply wipe down the surface using a clean, damp cloth and it is all good.
Hospital floors are sometimes wet and slippery, which means slips and falls are a concern. To prevent accidents caused by slipping and falling, you need to walk with caution. Crocs’ soles are engineered to provide excellent traction, and they will let you walk confidently and easily on wet/slippery floors.
See also: Best Slip-On Shoes for Nurses
For all these reasons, it is clear that Crocs make superb nursing shoes or any other vocation that requires prolonged standing and walking. However, since some hospitals have banned them due to safety concerns, it is a good idea to check with the hospital’s management and the dress code recommended. If your hospital allows the use of Crocs, then they are a fantastic option as they provide all-day support and comfort.


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Shop locally made goods at the Bayview Community Market!
The Bayview Community Market hosted at All Good Pizza is EVERY Saturday from May- October from 10am-2pm. There's something for everyone at this community centric market!
Shop Artisanal Food and Beverages: farm fresh organic produce + freshly milled pasta + pasta sauce gremolata olives + fresh baked pastries + delicious dumplings olive oil and vinegars + uniquely flavored puddings + local bread handmade jams and jellies + gourmet brittles + craft beer & wine adaptogen mixes + sweet and savory treats + brunch specials shaved iced lemonade and fruit drinks + neapolitan style pizzas delicious grilled paninis + fresh salads + weekly surprises!
Shop Arts and Crafts: up-cycled and tribal jewelry + hand-knitted kritter toys + candles baby & toddler beanies + lavender herb sachets + crocheted arts bespoke pet paintings created on-site + hand & body butter essential oils + craft kits + fabric shopping and produce bags beaded key lanyards + unique greeting cards + hair accessories flower arrangements + one of a kind gifts + clothing and shoes glass arts + garden creations + weekly surprises!

domain: food


The most powerful A-Class ever is getting closer and closer to its launch date. These are the most revealing photos of the hot entry-level model from Mercedes-Benz which is expected to feature the AMG Sport styling package which is available for the standard variant. There are a few differences, such as the larger 18-inch multi-spoke alloys, the trapezoidal tailpipes and the honeycomb grille inserts. However, what’s hiding under the hood is totally different as AMG’s engineers have put in a lot of work for creating a powerful A-Class with a 4-cylinder 2.0-liter turbo engine with direct-injection.
Earlier this year, the officials from the German automaker said that the power unit will be tuned to output somewhere around 330 hp and more than 295 lb-ft of torque, but AMG has managed to do an even more impressive job than that, increasing output to 350 hp and 332 lb-ft. In other words, it’s more powerful than the Audi RS3 Sportback with its 335 hp and also more potent than the BMW M135i which pumps out 315 hp.
This powerful engine will be connected to a seven-speed AMG SPEEDSHIFT DCT dual clutch transmission which will transfer the power to all four wheels. As you would expect, the chassis has been reworked and there’s a new suspension, while the steering system has been updated as well.
The Mercedes-Benz A45 AMG is expected to make its official debut in March 2013 during the Geneva Motor Show, before going on sale later on that same year. It will not be offered in the United States because for that market Mercedes will offer the CLA 45 AMG.


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Our Norwegian Made/Kvist&Kvae silver cone pendant in Tara Magasine.
Read about the little spinning mill of Telemark here.
Norwegian Made collaboration
In collaboration with the jewelry maker Kvist & Kvae, Norwegian Made has designed a silver pendant and earrings based on our logo. We couldn't be happier with the result!
You can buy the jewelry Kvist & Kvae's webshop.
We have great plans for this little tag.. We'll tell you more about it later.

domain: design


Solange is a woman of many talents, so it’s only right that she was asked to put together a video that shined a light on the finalists for the 2021 International Woolmark Prize. According to the award’s website, The International Woolmark Prize “celebrates outstanding fashion talents from around the globe who showcase the beauty and versatility of Australian Merino wool. It is the world’s most prestigious award for rising fashion stars.” The 2021 finalists for the award include Bethany Williams, Kenneth Ize, LECAVALIER, Matty Bovan, Thebe Magugu, and Casablanca.
The singer’s short film, titled Passage, features a cast of celebrities who wear clothing designed by the finalists for the International Woolmark Prize. Dionne Warwick rocks clothing created by Magugu while Dominique Jackson from FX’s Pose is found in work by Kenneth Ize. Rapper SahBabii and singer KeiyaA also appear in the visual directed by Wu Tsang. In a lengthy statement, Solange spoke about Passage and her inspiration behind the film.
In continuing Saint Heron’s world-making practice, Passage further explores my interest in theatrical production through the translation of identity, spirit, philosophy and creation. Whether it be through album artwork, stage design, or filmmaking, I’ve always sought to create new visual languages that encompass the expressions my other works cannot communicate. I’m inspired to expand these processes through the Saint Heron Agency with a wider scope of collaborations and projects. To reflect on and honor the creative process with the 2021 International Woolmark Prize finalists, Passage aligns with Saint Heron’s mission to reverence creation as life, from abstraction to being. I’ve been a longtime fan of Wu Tsang’s work and to be able to work alongside her, the Saint Heron team, and all of the incredible artists and designers in the film, really fortifies the ethos of collaboration and communal creative exchange that we wish to continue to embody.
You can watch the film in the video above.
Dionne Warwick is a Warner Music artist. Uproxx is an independent subsidiary of Warner Music Group.


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Weʼve raised £295 to help fund an event to support the Archer Project
- Funded on Friday, 10th February 2017
Crowdfunding is a new type of fundraising where you can raise funds for your own personal cause, even if you're not a registered charity.
The page owner is responsible for the distribution of funds raised.
On the 6th of December I will be sleeping rough all night. I am doing this to support the CATHEDEREAL ARCHER PROJECT and to raise awareness of the significant number of homeless people in England. Making the experience more difficult will the freezing sub-zero temperatures in December.
I am looking to raise money to put on an event to support the CATHEDRAL ARCHER PROJECT by experiencing what homeless people have to go through on a daily basis.
The CATHEDRAL ARCHER PROJECT is a charity based in Sheffield that helps homeless people every single day. Its primary aim is to help homeless people change their lives for the better. Life should be rewarding and enjoyable. Homelessness is neither.
The charity helps homeless people by:
- Developing independence
- Improving their ability to tackle setbacks
- Improve their ability to identify and change negative behaviour
- Improve wellbeing
The charity acknowledges that everyone’s needs are different, it combats complex problems day to day by offering: 1-1 support, an in-house nurse and dental practice, the ability to learn new skills and gain accredited awards. As you can imagine all of this needs significant funding.
Like many of you reading this I have been fortunate enough to have a supportive and loving family and always had a roof over my head. However there are a significant number of people who aren’t as fortunate as us.
Whilst we are all now starting to think about the festive period and being with our families, it is the HARDEST month for homeless and vulnerable people not just because of the cold.
Every penny helps so please donate what you can to this very worthy cause to support homeless people in Sheffield. THANK YOU!!!
Updates appear here
Sophie Henry started crowdfunding
Leave a message of support
Dec 8, 2016
Soph, amazed you did this, such a good cause. All the best for the event girlie!
Dec 7, 2016
Well done on supporting a great charity!
Dec 7, 2016
I am so proud of you Sophie! Amazing effort for an amazing cause! Well done pretty girl!Lots of love x
Dec 6, 2016
Well done youA fantastic effort
Dec 4, 2016
Nov 30, 2016
Good Luck Sophie!
Nov 30, 2016
Crowdfunding stories like this
Great people make things happen
Do you know anyone in need or maybe want to help a local community cause?
Create you own page and donʼt let that cause go unfunded!About Crowdfunding

domain: sociology


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It’s official. COVID-19 is no longer a national public health emergency. It ended today just six days after the World Health Organization announced that it is no longer a global public health emergency.
While most people think that the greatest effect of the end of the emergency has to do with COVID-19, they’d be wrong. The public health emergency also granted people who were on Medicaid peace of mind in their health coverage. While the public health emergency was in effect, they couldn’t lose their Medicaid coverage, even if their circumstances changed and they were no longer eligible.
With the public health emergency ending today, that means that folks will need to take action to ensure that they have medical insurance coverage. Many people are still eligible for Medicaid and only need to renew it. Others who are no longer eligible will have to find private insurance and can use the state’s Pennie marketplace to do so.
To make sure you keep your Medicaid insurance:
- Update your information in COMPASS or call 1-877-395-8930 or 1-215-560-7226 for help.
- 3 ways to renew:
- Look for your renewal forms in the mail and complete it.
- OR complete your renewal in COMPASS.
- OR call 1-866-550-4355 to renew by phone.
Help is available:

domain: medical


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PETA rallies behind Knoxville's Sunspot restaurant, puts burger in Top 10
People for the Ethical Treatment of Animals often makes waves for their combative statements and stunts in their sometimes-controversial battles on behalf of animals.
But this week PETA is showing nothing but love … for vegan burgers. And they’re raining that affection down on Knoxville’s Sunspot restaurant, which they deem features one of the Top 10 vegan burgers in the United States.
Sunspot’s Black Bean Burger has long been a fixture on the vegetarian/vegan-friendly Cumberland Avenue restaurant’s menu. It features house-made burgers consisting of quinoa, portabella mushrooms and beets and served with chipotle mayo, guacamole, tomato, arugula and cucumber. (They’re so good that even meat-eaters regularly order them.)
Sunspot was one of only two restaurants in the Southeast to make the list (the other is Kahiau’s in Virginia Beach, Virginia), which features multiple California and New York eateries. PETA said the winners were nominated and then evaluated by PETA staffers on a "coast-to-coast taste-testing mission."
PETA noted Sunspot’s previous accolades for its vegetarian menu, brunch, lunch and wine list. The Cumberland Avenue restaurant offers other vegetarian items including a tofu melt, hummus plate, soups and salads, fried avocado tacos, and a chili mac Impossible burger.
PETA didn’t mention that Sunspot also offers a considerable variety of meat-based items – from citrus marinated shrimp to smoked brisket tacos to grilled salmon to actual beef burgers. But of course that’s not the kind of thing PETA gets behind.
Sunspot is owned by Knoxville restaurateur Randy Burleson, whose Burleson Brands restaurants also include Aubrey's, Barley's, Bistro By The Tracks, drink., Fieldhouse Social and Stefano's Pizza.


text: Sheridan College men's basketball head coach Steve Smiley announced today the signing of Logan, UT native Grayson Moore to a letter of intent. Grayson is a 6'5", 170 pound wing from Skyview High School in Logan, UT. He is the son of former Utah State great and NBA player Jimmy Moore. Grayson's high school team finished the year with a 15-7 record while he averaged 14 points, 6 rebounds, 5.2 assists, and 2.3 steals a game. In Skyview's Regional Championship win against Box Elder High School last year Grayson scored 29 points, 9 rebounds, 6 assists, and 4 steals. Grayson is equally talented off the court where he holds a 3.9 GPA and will bring in numerous college credits. He and his family are good friends with former Sheridan College stand out Omar McDade in Logan, UT. The Sheridan College family is very excited for Grayson to arrive on campus this coming year and adding to the storied tradition that is SC Basketball!

domain: news


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Back to Journals » Journal of Inflammation Research » Volume 14
Grape Seed Proanthocyanidin Extract Moderated Retinal Pigment Epithelium Cellular Senescence Through NAMPT/SIRT1/NLRP3 Pathway
Authors Wan W, Zhu W , Wu Y, Long Y , Liu H, Wan W , Wan G , Yu J
Received 16 February 2021
Accepted for publication 24 June 2021
Published 12 July 2021 Volume 2021:14 Pages 3129—3143
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Ning Quan
Wencui Wan,1,* Wei Zhu,2,* Yan Wu,3,4,* Yang Long,1 Hongzhuo Liu,1 Weiwei Wan,1 Guangming Wan,1 Jing Yu3
1Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Ophthalmology, Changshu No. 2 People’s Hospital, Changshu, People’s Republic of China; 3Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, People’s Republic of China; 4Mois Biotech Company, Shanghai, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Guangming Wan
Department of Ophthalmology, First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, Henan, 450052, People’s Republic of China
Email [email protected]
Jing Yu No. 301, Yanchang Road, Shanghai, 200072, People’s Republic of China
Email [email protected]
Background: Retinal pigment epithelium (RPE) cellular senescence is an important process in degenerative retinal disorders. Grape seed proanthocyanidin extract (GSPE) alleviates senescence-related degenerative disorders; however, the potential effects of GSPE intake on RPE cellular senescence through regulating NAMPT/SIRT1/NLRP3 pathway remain unclear.
Methods: The effects of GSPE on NAMPT expression and NAD+ contents were detected with Western blot and assay kit in both in-vivo and in-vitro AMD models. Senescence-related biomarkers, including p16, p21 expressions and β-gal staining, were conducted in different groups. The protective effects of GSPE treatment on the mitochondrial homeostasis and barrier function of RPE cells were detected using mtDNA lesions analyses, JC-1 staining, ZO1 staining and trans-epithelial cell resistance (TEER) detection. The expression of senescence-associated secretory phenotype (SASP) in different groups would be conducted with qPCR. To demonstrate the potential effects of NAMPT/SIRT1/NLRP3 pathway after GSPE treatment, the protein levels of relevant key regulators after applications of NAMPT inhibitor, Fk866, and SIRT1 inhibitor, EX-527.
Results: GSPE significantly improves the NAMPT expression and NAD+ content in aging mice, and thus alleviates the RPE cellular senescence. In advanced in-vitro studies, GSPE significantly up-regulated NAMPT content and thus relieved H2O2 induced NAD+ depression through analyzing the NAD+ contents in different groups. In advanced analyses, it was reported that GSPE could alleviate mitochondrial permeability, mtDNA damage, ZO1 expression and SASP levels in aging RPE cells. Thus, GSPE treatment significantly decreased senescence-related protein p16 and p21, as well as SASP levels in in-vitro aging model, and it was demonstrated that GSPE could illustrate a significant anti-aging effect. The Western blot data in GSPE treatment of aging RPE cells demonstrated that GSPE could significantly improve NAMPT and SIRT1 levels, and thus depressed NLRP3 expression.
Conclusion: This study indicated that GSPE alleviated RPE cellular senescence through NAMPT/SIRT1/NLRP3 pathway. This study highlighted the potential effects of GSPE on degenerative retinopathy through the crosstalk of NAD+ metabolism, SIRT1 function and NLRP3 activation.
Keywords: cellular senescence, retinal pigment epithelium, nicotinamide phosphoribosyltransferase, sirtuin 1, inflammasome, NLRP3
Cellular senescence, which is an important cause of physiological and pathological changes in the ocular structure including the retina, is responsible for the development of diabetic retinopathy (DR), retinitis pigmentosa (RP) and age-related macular degeneration (AMD).1 The senescence-related retinal degenerative disorders affect the visual functions of more than 500 million patients and even lead to blindness in severe cases.2 RPE is a polygonal cell layer located between the choroid and neuroretina. The dysfunction of RPE is regarded as a key factor leading to the occurrence of AMD, DR and RP.3,4 The senescence of RPE cells will impair its phagocytosis and barrier function, along with abnormal secretion of neurotrophic and angiogenic factors.5,6 Therefore, clarifying the mechanism of RPE cell senescence will help to deepen the understanding of the pathological mechanisms of retinal degenerative diseases, and thus provide clues for the new drugs development for retinal disease, which remains a major problem that needs to be solved urgently.
Nicotinamide adenine dinucleotide (NAD+), which is the core cofactor of mitochondrial function, plays a vital role in regulating cell metabolism and energy homeostasis. NAD+ has been reported to be a potential target of the current anti-aging field.7,8 The decline of NAD+ content with age is closely related to the occurrence of age-related degenerative diseases;7,9 thus, NAD+ improvement would be a potential anti-aging therapy. In blue-light induced retinal damage (DR), as well as genetic glaucoma animal models, it is found that NAD+ contents in the retina samples were significantly decreased, and exogenous NAD+ supplementation could significantly prevent age-related NAD+ decrease and retinal dysfunction.10,11 A recent study analyzed the metabolic pathways in the RPE samples of AMD patients and it was found that NAD+ is decreased significantly. Nicotinamide phosphoribosyltransferase (NAMPT), also known as visfatin and pre-B cell enhancing factor (PBEF), is a rate-limiting enzyme that catalyzes the synthesis of nicotinamide into nicotinamide mononucleotide (NMN). NMN is the direct precursor of NAD+ in the NAD salvage synthesis pathway and could be transformed into NMN directly.12 In retinal degenerative diseases, the expression of NAMPT and the NAD+ content is consistent and reduced compared with the healthy controls. Therefore, we conjecture that abnormal NAD+ metabolism is involved in RPE cellular senescence, and thus the key regulatory factors of NAD+ metabolic pathway, NAMPT, is related to the development of retinal degenerative disorders.
Grape seed proanthocyanidin extract (GSPE) is extracted from whole grape seeds and regarded as an important source of polyphenolic bioflavonoid.13,14 As reported in the previous studies, GSPE exhibits antioxidant, anti-inflammatory, and anti-aging properties.15,16 GSPE could up-regulate the NAMPT expression,17 however, the potential protective role of GSPE induced NAMPT expressions in the RPE cellular senescence has not been studied. Therefore, based on these mentioned viewpoints, we hypothesize that GSPE treatment could inhibit the RPE senescence through up-regulation of NAMPT. Advanced in-vivo and in-vitro experiments would be conducted to detect the effects of GSPE on the RPE cell function as well as the potential pathological mechanisms through NAMPT/SIRT1/NLRP3 pathway.
The GSPE with over 98% proanthocyanindin purity was purchased from Rongsheng Biotechnology Co., Ltd. (Cat No.: 84929–27-1; Xi’an, China) and dissolved in drinking pure water for in-vivo study and in DMSO (Cat No.: C6164, Signa, USA) for in-vitro treatment. NAMPT inhibitor, Fk866 (Cat No.: F8557), and SIRT1 inhibitor, EX-527 (Cat No.: E7034), were purchased from Sigma (Sigma-Aldrich, USA). The NAD+ precursor, NMN with a purity of over 99.5% was purchased from Hygieia Biotechnology Co., Ltd (Cat No.: XJY01210128, Shenzhen, China).
All animal experiments were conducted in accordance with the Association for Research in Vision and Ophthalmology Statement for use of Animals in Ophthalmic and Vision Research. The animal protocol was approved by the Animal Ethics Committee of Zhengzhou University. Both male and female C57BL/6J mice of different age groups were obtained from a commercial vendor (Sipuer-Bike Laboratory, Shanghai). The mice would be housed under a pathogen-free environment with a 12:12 h light/dark cycle and free access to laboratory chow and water. Animal rooms were maintained at 20–22°C with 30%–70% relative humidity. Peripheral blood samples were collected and plasma was isolated and stored in −80°C until use. Besides, ocular samples were collected and then RPE was isolated gently from the choroidal layer in accordance with the previous study in different time points.18 The obtained animal samples were stored in −80°C until advanced experiments. GSPE treatment would be conducted through adding GSPE to drinking water and GSPE treatment conducted in the 15 months aged mice. After three months of GSPE treatment, the 18 months aged mice would be used in the following experiments.
The ARPE19 cells were purchased from American-type culture collection (Cat No.: CRL-2302, ATCC, USA) and cultured with Dulbecco’s modified Eagle medium/F12 (DMEM/F12) (Cat No.: SH30023.01B, HyClone, USA) supplemented with 10% heated-inactivated fetal bovine serum (FBS, Cat No.: 10099–141, Gibco, USA), 100 U/mL penicillin, and 100 μg/mL streptomycin (Cat No.: 15140–122, Gibco, USA). The ARPE-19 cells would be maintained at 37°C in a humidified chamber with 5% CO2 and 1:3 subcultures were conducted using trypsin-EDTA solution (Cat No.: 15140–122, Gibco, USA).
Total RNA from both animal examples and cultured cells were extracted with Trizol reagent (Cat No.: 15596026, Invitrogen, USA) following the manufacturer’s protocol. cDNA synthesis was conducted using Transcriptor First Strand cDNA Synthesis Kit (Cat No.: 04896866001, Roche, USA). RT-PCR was performed with Applied Biosystem™ SYBR™ using the TaqMan Multiplex Real-Time PCR Solution (Cat No.: 4367659, Thermo, USA) according to the manufacturer’s instructions. Relative mRNA expressions would be calculated with the ΔΔCt method. The primers used in this current study were listed in Supplemental Table 1. Three independent experiments were conducted for each sample and relevant results were used in advanced analyses.
The NAD+ contents in both animal samples and cellular homogenates were detected using a commercial NAD+ assay kit (Cat No.: MAK037, Sigma-Aldrich, USA). All the experiments were conducted according to the manufacturer’s instructions.
The in-vitro aging model of RPE cells was generated according to a protocol previously described in our lab19 with slight modifications. In general, the APRE-19 cells were placed in petri dishes, and then exposed to 800 µM H2O2 for 2 hours at 37°C for five consecutive days. After that, the medium would be replaced with Fresh complete media after H2O2 treatment. The aging RPE cells would be collected in the other day after the last H2O2 treatment and the aging in-vitro model would be used in the following studies.
The cell viability was detected in this study with MTT assay. MTT dye (Cat No.: M1025, Solarbio, China) was added to the 96-well plate with ARPE-19 cells in different groups and incubated for four hours at 37°C. After replacing the culture media with 150 µL of DMSO to each well, the 96-cell plates were shaken thoroughly until the crystals dissolved. Absorbance was measured at a wavelength of 490 nm using the Thermo Scientific Fluorescent microplate reader (Thermo Fisher Scientific, USA). Three independent experiments were conducted for each group and data were used for advanced analyses.
Cellular senescence marker, β-galactosidase (β-Gal) activity, was used in the measurement of senescent status in different cell models, and the assay was performed with a commercial assay kit (Cat No.: C0602: Beyotime Biotechnology, China) according to the manufacturer’s protocols. The view and counting would be conducted under the brightfield of the Leica Microscope (Leica Biosystems, Germany). The senescent cells expressing SA β-gal were positive cells and stained blue. Positive cell rates were recorded in each group and the data would be used in advanced analyses.
As NAD+ was an important contributor to DNA damage repairment, the mtDNA lesion measurement was conducted in each group. The detection of mtDNA was performed using a well-validated QPCR-based detection assay, as previously described.20 The DNA extraction was conducted using a genomic-tip kit (Cat No.: 10043, Qiagen, CA) and the extracted DNA would be stored in −80°C before experiments. The principle of mtDNA lesion measurement was that any lesion on a DNA template would block the function of thermostable polymerase and therefore only the DNA templates without any DNA damages could be amplified. After DNA templates quality control, the qPCR would be conducted with a High-Stability PCR Kit (Cat No.: E00043, GenScript, China). The β-globin product was used as an inner-control for the detection of relative mtDNA lesion as described previously. Three independent experiments were conducted with three repetitions.
The JC-1 dye accumulated in the mitochondria in a potential-dependent manner and thus could be used to detect the membrane potential of cells, tissues or purified mitochondria. JC-1 was an ideal fluorescent probe widely used to detect the ΔΨm position of mitochondrial membrane (Cat No.: C2006, Beyotime Biotechnology, China). After aspirating culture media in the 6-well plate and washing the cells with PBS, 1 mL of JC-1 dye working solution was added into each well. After incubating the mixed working system for 20 minutes at 37°C, the cells would be washed with the JC-1 Buffer (1×) and placed on ice. The cells would be observed under a confocal microscope (Leica, Germany). The polymer emits strong red fluorescence (Ex=585 nm, Em=590 nm) and the monomers produced green fluorescence (Ex=514 nm, Em=529 nm). The fluorescence rate of monomers/polymer was detected and analyzed.
Trans-epithelial cell resistance (TEER) was conducted to identify the cellular permeability with TEER24 (Applied Biophysics, USA). ARPE-19 cells were inoculated on the bottom membrane of the upper layer of the transwell chamber (0.3×104/well), and 1.2 mL of the complete cell culture medium was added to the chamber. The TEER was measured after the cell was confluent. After debugging the TEER24 epithelial volt ohmmeter and wiping the electrode pads with alcohol, the electrode sheets were immersed into the inner and outer culture medium, respectively. The resistance of the blank control group (without any cells inoculated) and the experimental group was measured vertically in sequence. The measurement was repeated three times for each hole, and three multiple holes were set for each group. Calculation of TEER value was conducted as following: TEER=(resistance value experimental group-resistance blank control) ×0.3 and the unit was Ω/cm2.
After plating the ARPE-19 cells onto six-well plates and generating cells grown on a coverslip, the coverslip was washed once with a PBS buffer, and then the cells would be fixed for 20 min at room temperature. To break the membrane, 0.2% Triton X-100 was added following with three times washes with PBS. Incubation with blocking solution (PBS containing 10% goat serum) was conducted for 2 h at 4°C and then the cells would be incubated with dilute primary antibody (anti-ZO1, Cat No.: ab221547, Abcam, UK; anti-NLRP3, Cat No.: ab263899, Abcam, UK) for immunostaining in a cold room overnight. The cells were washed three times with PBS and then the secondary antibody was added to incubate with the cells for 1 h in the dark. Drop the DAPI & anti-quencher mixture onto the glass slide and flip the cover glass. Observation and record of the immunofluorescence photographs were conducted with a Zeiss confocal microscope (Leica Biosystems, Germany) under dark.
After extracting the total protein from tissues and cellular samples using RIPA buffer with protease inhibitors, BCA quantitative measurements of protein concentrations were conducted. The relative expressions of the target proteins were normalized to β-actin. A total of 20 μg protein for each sample was separated by SDS-PAGE and transferred onto PVDF membrane (Cat No.: IEVH00005, Millipore, USA). After incubating with the milk in TBS for blocking, the membrane would be incubated the corresponding primary antibody, including anti-p16INK4a (Cat No.: ab108349, Abcam, UK), p21Waf/Cip1 (Cat No.: ab109520, Abcam, UK), SIRT1 (Cat No.: 2310, Cell Signaling, USA), NLRP3 (Cat No.: ab263899, Abcam, UK), apoptosis-associated speck-like protein (ASC, Cat No.: 13833, Cell Signaling, USA), pro-caspase-1 (Cat No.: ab179515, Abcam, UK), caspase 1 (Cat No.: ab207802, Abcam, UK) and β-actin (Cat No.: sc-47724, Santa Cruz, USA), at 4°C overnight. On the second day, the membrane was washed three times with TBST and incubated with the secondary antibody (Cat No.: sc-2357 and sc-2005, Santa Cruz, USA) for 1 h. The density of the bands was quantified using Labworks image acquisition software (UVP, USA) and was quantized using ImageJ software (NIH, USA).
The production of IL-1β and IL18 of ARPE-19 cells in different groups was measured using IL-1β (Cat No.: PI305, BioPioneer Tech, China) and IL-18 (Cat No.: PI558, BioPioneer Tech, China) ELISA kit according to the manufacturer’s instructions. Samples were quantified with a corrected value of 450 and 570 nm using the absorbance measurements in the Thermo Scientific Fluorescein microplate reader (Thermo Fisher Scientific, USA). Three replications for all the samples were adopted and the data of three independent studies were used in the final analyses.
In this study, the data were presented as a mean ± standard deviation (SD). The non-paired t test would be used for the difference detection non-paired t test, and one-way analysis of variance (ANOVA) followed by the Newman-Keuls method for multiple comparison analysis test among over two groups was used for analyses. The P value < 0.05 denotes statistical significance.
NAD+ metabolism was a key regulator in the increasing of aging and salvage pathway provided about 85% of total NAD+. As described in Figure 1A, NAD+ was transformed into NAM through NAD+ consume. Then, the NAM would be transformed into NMN after being catalyzed by NAMPT. NMN would then be used in NAD+ synthesis by NMNAT1-3 enzyme and thus the NAD+ salvage metabolism cycle was completed. Compared with the young mice (2 months aged), lower NAMPT expression in 18-month aged mice and decreased NAD+ contents in 12- and 18-months aged mice were detected (P<0.05). After supplementing 250 mg/kg GSPE from 15 to 18 months age, a significant increased NAMPT expression and improved NAD+ content was detected (P<0.05, Figure 1B and C). A similar expression pattern was observed in the mouse plasma and NAMPT/NAD+ levels decline was observed in the aging mice. The intake of 250 mg/kg GSPE for three months significantly improved the NAMTP expression and NAD+ content in plasma (P<0.05, Figure 1D and E).
Figure 1 Decreased NAMPT and NAD+ levels in RPE and plasma could be improved by GSPE treatment in aging mouse. (A) The salvage pathway of NAD+ metabolism: NAD+ was transformed into NAM through NAD+ consume, the NAM would become NMN after being catalyzed by NAMPT and NMN would also be transformed into NAD+ by NMNAT1-3 enzyme. (B-C) Compared with 2-month aged mice, NAMPT expression is reduced in 18-month aged mice, and NAD+ content is reduced in 12-month and 18-month aged mice. After supplementing with GSPE at a concentration of 250 mg/kg at 15 to 18 months of age, significant increase in NAMPT expression and NAD+ content. n=3, **: P<0.01. (D-E) The decrease of plasma NAMPT/NAD + level was related to the increased mouse age. Ingestion of 250 mg/kg GSPE for three months can significantly improve the content of NAMTP and NAD+ in plasma. n=3, **: P<0.01, ***: P<0.001.
To detect the protective effects of GSPE supplement in the aging mice, the expressions of cellular senescence-related markers, p16INK4a and p21Waf/Cip1, as well as the SASP contents were reported. As showed in Figure 2A, p16INK4a and p21Waf/Cip1 expressions were increased in the aging mice (18 months aged) and 250 mg/kg GSPE would decline these cellular senescence-related biomarkers. As SASP involved a series of pro-inflammatory factors, chemokines as well as proteases. Common SASP related biomarkers, including tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), interleukin-1β (IL1β), interleukin-6 (IL6), interleukin-8 (IL8), interleukin-18 (IL18), monocyte chemotactic protein 1 (MCP-1), granulocyte-colony stimulating factor (G-CSF), chemokine (C-X-C motif) ligand 1 protein (CXCL1), chemokine (C-X-C motif) ligand 2 protein (CXCL2), inositol requiring enzyme1α (Ire1α), plasminogen activator inhibitor-1 (PAI1), matrix metalloproteinases-1 (MMP-1), matrix metalloproteinases-3 (MMP-3) and tissue inhibitor of metalloproteinase-2 (TIMP-2) were detected. The differently expressed IL18, TGF-β1, IL1β, TIMP-2, MMP-3, IL8 and MCP-1 in the RPE tissues of the aging mice were detected (P<0.05). Most significantly regulated SASP were reserved by three months of GSPE supplementation and the visualized data as well as the detailed P values are presented in Figure 2B.
Figure 2 GSPE alleviated aging related cellular senescence and SASP in mouse RPE. (A) p16INK4a and p21Waf/Cip1 expressions were increased in the aging mice (18 months aged) and the GSPE in 250 mg/kg would decline these cellular senescence biomarkers. The representative western-blot gels and statistical results were presented. n=3, ***: P<0.001. (B) The SASP factors in the young, aging and aging mice treated with three-month GSPE supplementation. The expressions of TNF-α, TGF-β1, IL1β, IL6, IL8, IL18, MCP-1, G-CSF, CXCl1, CXCL2, Ire1α, PAI1, MMP-1 and MMP-3 were visualized by s heatmap. The lowest expression was marked as blue and the highest expression was marked as red. The P values of comparison of young vs aging as well as aging vs aging mice treated with GSPE were presented and any P values of significant differences were marked red (P<0.05). n=3.
To detect the effects of GSPE treatment in the normal and aging ARPE-19 cells, GSPE in different concentrations (0.1, 1, 10, 50 and 100 μg/mL) were applied in the in-vitro model. As showed in Figure 3A and B, GSPE failed to affect the cell viability of the normal ARPE-19 cells; however, 10 and more than 10 μg/mL of GSPE significantly improved the cell viability in the aging RPE cells. When the NAD+ contents and NAMPT expressions in the aging ARPE-19 cells were considered, a significant deceased NAD+ and NAMPT contents were observed in the aging RPE cells and these two NAD+ metabolism markers were up-regulated with 10 μg/mL or higher concentrations of GSPE treatments (P<0.001, Figure 3C and D). In advanced β-gal activity detection, it was found that β-gal activity was significantly increased in the aging RPE cells and the activity was alleviated by 10 μg/mL or higher concentrations of GSPE treatment (P<0.001, Figure 3E). The effects of GSPE on the cell viability, NAD+ metabolism and β-gal activity were consistent and the concentration of 10 μg/mL would be used in the following experiments.
Figure 3 GSPE extenuated RPE cellular senescence of the in-vitro model. (A-B) GSPE failed to affect the cell viability of normal ARPE-19 cells, while GSPE at 10 and 10 μg/mL significantly improved the cell viability of senescent RPE cells. n=3, ***: P<0.001. (C) NAD + content was decreased significantly in senescent RPE cells, and the NAD + content was up-regulated with 10 μg/mL or higher concentrations of GSPE treatments. n=3, ***: P<0.001. (D) The expression of NAMPT was decreased significantly in senescent RPE cells, and it was up-regulated with 10 μg/mL or higher concentrations of GSPE treatments. The representative western-blot gels and statistical results were presented. n=3, ***: P<0.001. (E) The β-gal activity is significantly increased in senescent RPE cells, and treatment with GSPE at a concentration of 10 μg/mL or higher reduces the activity. n=3, ***: P<0.001.
As NAD+ metabolism was closely related to mitochondrial homeostasis, the mtDNA lesions were detected with a classical PCR-based method. Besides, the mitochondrial membrane permeability was analyzed with JC-1 staining. As showed in Figure 4A, GSPE treatment significantly alleviated the mtDNA lesions, which was significantly increased in the aging RPE cells (P<0.001). Increased mitochondrial membrane permeability was related to the worsening mitochondrial function and it would demonstrate more monomers JC1 staining in the mitochondria. After GSPE treatment, the damaged mitochondrial membrane permeability was significantly improved (P<0.001, Figure 4B). Considering that the physiological functions of RPE cells included barrier function and growth factor secretions, the effects of GSPE treatment on the barrier function and SASP on aging RPE cells were reported in this study. Both the cellular barrier marker (ZO1) and barrier function (TEER) were detected in this study. It was reported that GSPE could significantly improve the expression of ZO1 and then reinstate the TEER in the aging RPE cells (P<0.05, Figure 4C and D). The abnormal growth factor secretions of RPE cells were related to the incidence of retinal diseases and SASP related factors were reported to be significantly improved in the RPE cells of the aging mice. In this study, significantly expressed TGF-β1, IL1β, IL6, IL8, MCP-1, G-CSF, CXCL2, MMP3 and TIMP-2 were detected (P<0.05, Figure 4E). Compared with aging RPE cells, GSPE treatment could significantly alleviate the expression of the most dysregulated SASP factors (P<0.05).
Figure 4 GSPE alleviated mitochondrial homeostasis, barrier function and SASP of aging RPE cells. (A) GSPE treatment significantly alleviated the mtDNA lesions, which was significantly increased in the aging RPE cells. n=3, ***: P<0.001. (B) After GSPE treatment, less monomer J1 stained, and the permeability of the damaged mitochondrial membrane was significantly improved. The J1 monomers were stained green and J1 aggregates were stained red. n=3, P <0.001. (C) GSPE could significantly improve the expression of ZO1 in the aging RPE cells. ZO1 was stained read and the nuclear was stained blue with DAPI. n=3, P <0.001. (D) GSPE treatment significantly improve the reinstate the TEER in the aging RPE cells. n=3, *: P<0.05. (E) Significantly expressed TGF-β1, IL1β, IL6, IL8, MCP-1, G-CSF, CXCL2, MMP3 and TIMP-2 was detected and GSPE could significantly alleviate the expressions of most dysregulated SASP factors comparing with the aging RPE cells. *: the comparison of aging and normal groups. #: the comparison of aging with GSPE treatment groups and aging groups. * and #: P <0.05, ** and ##: P <0.01, *** and ###: P <0.001.
As demonstrated in Figure 5A, the protective effects of GSPE on cellular senescence in aging RPE cells were blocked by NAMPT inhibitor, Fk866, while the supplementation of NMN significantly reinstated the protective effect. Advanced study on the NAD+ status demonstrated that GSPE treatment demonstrated potential anti-aging effects through up-regulation of NAD+ contents (Figure 5B). As NAD+ was an important substrate of SIRT1, the effects of GSPE treatment on the NAMPT/NAD+/SIRT1 pathway in aging RPE cells were detected. It was found that GSPE treatment significantly up-regulated the expression of SIRT1 and this regulation effects were modified by NAMPT inhibitor, Fk866, and NAD+ precursor, NMN (P<0.05, Figure 5C).
Figure 5 GSPE regulated NAMPT/SIRT1 pathway in aging RPE cells. (A) The NAMPT inhibitor Fk866 blocked the protective effect of GSPE on senescent RPE cells, while supplementing with NMN significantly restored the protective effect. n=3, P <0.001. (B) GSPE demonstrated potential anti-aging effect through up-regulation of NAD+ content. n=3, P <0.001. (C) GSPE treatment significantly up-regulated the expression of SIRT1 and this regulation effects were modified by NAMPT inhibitor, Fk866, and NAD+ precursor, NMN. The representative western-blot gels and statistical results were presented. n=3, ***: P <0.001.
Inflammasome was associated with the incidence of various degenerative retinal disorders, the effects of GSPE on the inflammasome activity and the potential molecular mechanism was studied in this study. As showed in Figure 6A, significantly increased NLRP3 expression was detected in the aging RPE cells and GSPE treatment reduced the NLRP3 expression after 24 or more hours treatment (P<0.001). In the advanced experiments, 24 hours of GSPE treatment was used in the following mechanism detections. Since the regulatory effects of SIRT1 were reported in the previous experiments, the potential molecular mechanism of GSPE up-regulating SIRT1 and inhibiting inflammasome activity was studied. The treatment of GSPE significantly extenuated inflammasome activity and the key compounds, including NLRP3, ASC and caspase-1, were significantly alleviated by GSPE treatment in the aging RPE cells. While the suppressed NLRP3 pattern in the NMN treated aging RPE is impaired by SIRT1 inhibitor, EX-527 treatment and the detailed data are presented in Figure 6B. IL-1β and IL-18 were two cytokines related with the NLRP3 activation and it was found that the inhibitory effects of GSPE treatment on the IL1β and IL-18 secretions were disturbed by the SIRT1 inhibitor, EX-527 (Figure 6C).
Figure 6 GSPE alleviated the inflammasome activation through SIRT1 in aging RPE cells. (A) significantly increased NLRP3 was detected in the aging RPE cells and GSPE treatment reduced the NLRP3 expression after 24 or more hours treatment. The NLRP3 was stained greed and the nuclear was stained blue with DAPI. n=3, P <0.001. (B) The treatment of GSPE significantly reduced the activity of inflammasomes such as NLRP3, ASC and caspase-1, and was significantly relieved in aging RPE cells. While SIRT1 inhibited the NLRP3 regulation mode, it was processed with EX-527 and provided detailed data. The representative western-blot gels and statistical results were presented. *: the comparison of aging and normal groups. #: the comparison of aging with GSPE treatment groups and aging groups, &: The comparison of aging with GSPE+EX-527 treatment groups and aging with GSPE groups. n=3, *, # and &: P <0.05, **, ## and &&: P <0.01, ***, ### and &&&: P <0.001. (C) The inhibitory effects of GSPE treatment on the IL1β and IL-18 secretions was disturbed by the SIRT1 inhibitor, EX-527. n=3, P <0.001.
Cellular senescence was a major risk factor of the degenerative retinal disorders incidence.21 In this current study, GSPE consumption significantly increased the NAMPT expression and improved NAD+ contents in aging mice and thus alleviated the RPE cellular senescence. Aging would impair NAMPT function and lower NAD+ content was a cause of degenerative retinal diseases. In this study, advanced in-vitro studies demonstrated that GSPE could activate NAMPT expression and thus relieved H2O2 induced NAD+ depression. GSPE consumption could improve impaired mitochondrial functions in the aging RPE cells. By analyzing the effects of GSPE on SIRT1 and downstream inflammasome activity, it is demonstrated that GSPE demonstrates the protective effects in aging RPE cells through NAMPT/SIRT1/NLRP3 pathway (Figure 7).
Figure 7 GSPE ameliorated cellular senescence in the RPE cells and could be a potential therapy for degenerative retinal diseases. GSPE significantly up-regulated the NAMPT expression in the aging RPE cells and thus improve the production of NAD+. Up-regulated NAD+ improved the expression of SIRT1 and protected mitochondrial homeostasis, thus reducing SASP level. Improved cellular senescence status and lower SASP levels would be a retinal degenerative diseases.
AMD was the most common irreversible cause of severe vision loss among the elderly in developed countries. Advanced age was one of the mostly accepted risk factors of the AMD; thus, cellular senescence might be associated with the incidence of AMD.22 The detailed mechanism of the cellular senescence in AMD progression remained unclear. The decline of NAMPT and its metabolic product, NAD+, was reported to be related to aging progress in different organs and cells, including RPE.22 Exogenous NAD+ precursor, NMN, demonstrated a significant protective role in RPE cellular senescence.23 NAMPT, which was the rate-limiting enzyme of NAD+ metabolism and a potential target in the treatment of cellular senescence, might help to improve NAD+ concentration and thus played an important role in the field of anti-aging. GSPE, which is a grape seed extract, is rich in polyphenolic bioflavonoid. In this current study, it was found that GSPE could significantly improve the NAMPT expression as well as NAD+ content and thus protected the RPE cells from cellular senescence. NAD+ improvement had been regarded as an important approach; however, the most commonly used NAD+ supplement, NMN, was relatively expensive. Our study provided an economic NAD+ improvement therapy through up-regulation of the NAMPT expression in RPE tissues. The results of this study highlighted the importance of screening for more anti-aging natural extracts and would help to improve our understanding of their effects on aging-related degenerative disorders.
NAD+ improvement could effectively improve various degenerative disorders; however, previous studies mainly focused on the effects of NAD+ metabolism in retinal nerve cells, while less attention was paid to RPE cells. Considering that RPE senescence was a key process in various degenerative diseases,24 any treatment targeting RPE cellular senescence would provide huge effect on the management of these disorders. Rather than simply detecting the up-regulation of NAMPT and NAD+ by GSPE treatment, a more detailed molecular mechanism was studied. SIRT1 functioned based on the NAD+ activity and provided remarkable protections for retinal degenerative disorders.25,26 Based on the in-vitro experiments and molecular biological studies, it was found that GSPE application could significantly up-regulate the SIRT1 level.27 Inhibition of SIRT1 depleted the protective effects of GSPE significantly and it provided us the confirmation that SIRT1 was an important connection between GSPE treatment and the anti-aging effects in the RPE cells. As NAD+ was a powerful activator of SIRT1, it was easy for us to understand the extract molecular mechanism for the protective effects of RPE cellular senescence: GSPE treatment significantly up-regulated the NAMPT levels in the aging RPE cells and thus improved the production of NAD+. Up-regulated NAD+ improved the expression of SIRT1, which was a key factor in the anti-aging function during NAD+ intervention. This study presented a simple but clear clue of the anti-aging effect of GSPE in RPE senescence; however, the complex NAD+ and SIRT1 regulation system required to be studied in advanced experiments. For instance, NAMPT could transform Nicotinamide (NAM) into NMN and NAMPT up-regulation might lead to decreased NAM. NAM was an inhibitor of SIRT128 and NAM down-regulation might be associated with SIRT1 activator. More detailed experiments on the contributions of NAD+ metabolism and SIRT1 activity to the RPE senescence were to be conducted.
Cellular senescence would lead to increased inflammatory cytokines expressions and this phenomenon was defined as SASP.29,30 SASP was composed of a series of cytokines, including pro-inflammatory cytokines, growth factors, chemokines and matrix remodeling enzymes. The increased SASP could cause chronic low-grade inflammation and accelerate the aging progresses in both cells and organs.31,32 More and more evidence demonstrated that the chronic low-grade inflammation was one of the most important manifestations of AMD.33 Although the precise mechanism had not been fully determined so far, we speculated that SASP was a link between aging and AMD. In this current study, the SASP markers were significantly increased in the aging mice and senescent RPE in-vitro models; thus, it provided evidence that SASP could be regarded as a key biological process for AMD development. Advanced experiments demonstrated that GSPE could reduce SASP status significantly. As SASP was both a hallmark and promoter of cellular senescence, GSPE could efficiently alleviate the retinal degenerative disorders by moderating SASP in aging senescence.
The physiological functions of RPE cells included growth factor secretion, blood-retinal barrier (BRB) maintenance and outer disc membrane phagocytosis.34 Pathological stress, such as aging, would lead to the loss of physiological functions and thus cause advanced pathological changes. Abnormal growth factor secretion of RPE was one of the most common pathological progresses and it would lead to neovascularization in choroidal (wet AMD) and retina (proliferative DR).35,36 RPE was the outer BRB and impaired RPE tight junction would cause retinal edema, such as macular edema secondary to DR.37 Both neovascularization and retinal edema were two important causes of blindness for patients with retinal disorders. In this current study, it was found that GSPE treatment could moderate the abnormal SASP levels as well as impaired BRB by alleviating RPE cellular senescence. Thus, GSPE supplement could be a potential treatment for the AMD and DR cases. More advanced experiments in diseased animal models and clinical trials in patients with the degenerative retinopathy would help us to understand the drug development potential of GSPE.
Based on the experimental data, two important cytokines, IL1β and IL8, were alleviated by GSPE treatment in both in-vivo and in-vitro aging models. Interestingly, these two cytokines were key effectors in the inflammasome activation.38,39 Inflammasome was a complex composed of multiple proteins, which could activate the protease caspase-1. Caspase-1 protease cleaved pro-IL-1β and pro-IL-18, activated them, and released active IL-1β and IL-18. As reported in previous studies, inflammasome was activated in degenerative retina, including AMD, DR and glaucoma.40,41 Previous studies on the effects of SIRT1 on the inflammation activation demonstrated that SIRT1 could moderate the inflammation activity significantly. Based on the results of a myocardial ischemia and reperfusion (I/R) mice model, SIRT1 agonist could reduce NLRP3 inflammasome activation during I/R.42 Combining the existing knowledge and experimental data in this study together, we could conclude that SIRT1 induced by GSPE was associated with the moderation of inflammasome activation during RPE cellular senescence. Considering that mounting evidence was reported on the relationship between inflammasome and cellular senescence in degenerative diseases, the findings in this study provided a new viewpoint on the crosstalk on the NAD+ metabolism and SIRT1/NLRP3 pathway in the RPE senescence.
This study had conducted the effects of GSPE in combination with NMN in RPE cellular senescence. An old age mouse animal model was used in this study, and it demonstrated the potential benefits of GSPE and NMN in retinal degeneration. Besides, we would conduct more advanced studies on the RPE cellular senescence-related disorders, including AMD, DR and RP. By analyzing the protective effects of NMN and GSPE treatments on other tissues, this would provide us with more knowledge.
In conclusion, this study has uncovered the protective effects of GSPE on the RPE senescence through up-regulation of NAMPT expression and NAD+ concentration. NAD+ induced SIRT1 expression and then inhibited the activation of inflammasome complex during the process of RPE senescence. GPSE supplement provided a new potential therapeutic method in RPE senescence associated with retinal degenerative disorders.
This work was supported in whole or in part by the National Nature Science Foundation Project for Young Scientists of China (Grant No. 82000903, 81700804), the Foundation for Young Medical Talents of Jiangsu Province (Grant No. QNRC2016211), Scientific Research Project of Jiangsu Health Commission (Z2019044) and Youth Project of Henan Provincial Health and Health Commission, Ministry of Education (SB201902008).
Yan Wu is the founder of the Mosi Biotech Company. The authors report no other conflicts of interest in this work.
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domain: health


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Date of Conferral
Doctor of Education (Ed.D.)
School principals' leadership strategies and collaborative efforts contribute immensely to defining and managing goals in response to any educational initiatives, including social-emotional learning (SEL) programs. The problem prompting this study was the disproportionate special education referral and school suspension of minority students. Although the focus school district adopted an SEL curriculum and tasked principals with implementation to reduce disproportionality, these disparities continue to persist. This qualitative descriptive study explored 10 principals' leadership strategies and implementation challenges regarding SEL program implementation to close the disparity of special education identification and the suspension and expulsion of minority students at an urban school district in the state of California. Transformational leadership and implementation science frameworks guided this study. Data gathering sources included semi-structured interviews with 10 principals on their leadership behaviors and challenges in implementing SEL programs. For data analysis, I used the NVivo software to organized and stored the data. The findings indicate that clear communications with staff, setting manageable goals, and conducting need assessments that address the disparity and intervention selections were vital. Simultaneously, lack of staff commitments, inadequate professional development, and insufficient time for planning impedes principals' leadership to support SEL implementation at their schools. The results of this study may contribute to social change by informing school leadership on how to provide culturally responsive training for the best practices necessary to support diverse learners, promote proactive practices, and create positive school cultures using SEL.
Akinnusi, Margaret, "Understanding Principals' Perceptions of Leadership for Implementation of Social-Emotional Learning (SEL) Programs" (2021). Walden Dissertations and Doctoral Studies. 10473.

domain: literature


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Johnson & Johnson Announces New Center for Health Worker Innovation
Johnson & Johnson has announced a new Center for Health Worker Innovation to empower and strengthen the global health workforce. Johnson & Johnson hopes this will spur a movement to address the global health workforce shortage challenge.
The World Health Organization has declared that the world needs 18 million more health workers to accomplish universal health coverage and better health, especially for low and lower-middle income countries.
The Center for Health Worker Innovation will focus on giving nurses, midwives, and community health workers the skills necessary to work in their local communities around the world. Johnson & Johnson seeks to promote the skills of the health worker and give them the ability to work at their full potential. They will also support leadership and management programs for health workers to give them the skills to take on leadership roles.
The Center for Health Worker Innovation will also address the health worker gap, improve quality care and community-based health systems. Read the full Q&A with Johnson &Johnson from Devex.


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Firstly, welcome to itsiffy.com! After 5 long years, I’ve finally decided to change the name of my blog and give it the layout it deserves. I hope you guys enjoy this 2.0 version, where you can expect to find greater diversity in content. But you can read more about that here.
I wanted the first post on my ‘new’ blog to be about food because food is one of my biggest passions, and what better way to share the love of food than to share with you guys one of my most loved recipes, which (I think) I have finally perfected.
I really love halwa. It is basically a sweet dish which is served in a huge range of ways all across the world. In South Asia you will find sooji ka halwa (semolina based halwa), and in the Middle East, halwa tends to be made from tahini or other nut butters. I personally am a fan of all variations! I am passionate about fusion cooking – this basically involves mixing up the elements of different culinary traditions. It’s this ‘mixing up’ which was the main inspiration behind this recipe.
This recipe is ridiculously easy to make and the ingredients are healthy and nourishing. The flavours of the coconut combined with sesame, honey and pistachio go extremely well together – I actually prefer this non-conventional halwa more than the traditional types. These bars are delicious and chewy – once you eat one, I can guarantee you will find it hard to stop. I also made sure that my recipe is vegan-friendly because, although I am not vegan myself, I made the first batch of these for some friends who were.
– 2 tablespoons of coconut oil
– 2 tablespoons of honey
– 3/4 a cup of raw sesame seeds
– 3/4 of a cup of shredded, unsweetened coconut
– 1/2 a cup of pistachios (without shell)
– Vanilla pods to taste (optional)
1. Add all the ingredients except for the pistachios into a powerful food processor and blend blend blend. It should quickly collect together like a big dough.
2. Place into a tray lined with greaseproof paper/clingfilm and smooth into a rectangle.
3. Use a pestle and mortar to grind the pistachios, then sprinkle them all over the top of the halwa.
4. Cut into rectangular pieces (should make 12).
5. Place in the fridge until they harden (not into a complete solid). This shouldn’t take too long – approximately 30 minutes. The coconut oil in these bars will keep them slightly soft and deliciously chewy!
– If you prefer a sweeter taste, add more honey; for a less sweet taste, add more shredded coconut
– How much honey you use depends on the strength of your honey. If you are using strong raw honey, use less!
– Alternatively, you can place these in the freezer until they are solid. Personally I prefer to refrigerate them as I think they taste nicer when they are slightly soft and chewy rather than completely solid.


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Atlético Madrid 1-0 CF Reus Deportiu (3-1 agg)
Reus made life difficult for Atletico, though they never looked like upsetting the Liga BBVA side. The hosts created a string of chances throughout the first half but were unable to make the break-through. Ghanaian midfielder Thomas Partey volleyed home the game's only goal from outside the box after 53 minutes to secure Diego Simeone’s men a place in the next round.
RC Celta 1-0 UD Almeria (4-1 agg)
Celta, who had won 3-1 in the first leg, were comfortable winners at home against Almeria. Danish midfielder Daniel Wass scored from a freekick at the end of the first period to effectively end the tie as a contest.
Granada CF 1-0 CD Leganes (2-2 agg, Granada qualify on away goals rule)
The Andalusian side fought back from a 2-1 first leg deficit to go through to the next round. Liga Adelante side Leganes battled hard, but Moroccan forward Youssef El Arabi netted after 68 minutes to put Granada through on the away goals rule.
Villarreal CF 2-0 SD Huesca (4-3 agg)
Villarreal over-turned a 3-2 first leg deficit to knock out the Liga Adelante side. The team from Castellon were winning by half time with a goal from Manu Trigueros. In the second half, Roberto Soldado netted the decisive goal.

domain: sports


growgems.dy.fi is a subdomain of the domain dy.fi within the top level domain fi. The domain was registered on , and thus is old.
IP Addresses and Server Locations
growgems.dy.fi resolves to 18.104.22.168. According to our data this IP address belongs to Netcrew ry and is located in Finland. Please have a look at the information provided below for further details.
|Latitude||60.1708 / 60°10′14″ N|
|Longitude||24.9375 / 24°56′15″ E|
DNS Resource Records
|Fetching DNS Resource Records for dy.fi...|
WHOIS data for Dy.fi
|Fetching WHOIS data for dy.fi...|
|Response Code||200 OK|
Raw HTTP Header
HTTP/1.1 200 OK Server: nginx/1.4.1 Date: Fri, 15 Dec 2017 10:18:52 GMT Content-Type: text/html Transfer-Encoding: chunked Connection: keep-alive Keep-Alive: timeout=10 Set-Cookie: dyvisit=2zG9thw4ENMjWkvgZobg1vNxJs1bGBLsWp%2Fvbm%2Bg3V1O13PvvbbKDAXLI0RVNmC7; expires=Sun, 15-Dec-2019 10:18:52 GMT; path=/; domain=dy.fi Content-Encoding: gzip
Reverse IP Lookup - Hostnames at the same IP address
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99 Ford Alternator Wiring. Its very detailed and shows how every wire for each component routes to the PCM. 1-8 of 8 Results.
Duralast Pigtail Connector Harness 611 39. 73L Wiring Schematic Printable very handy. Length 6 Gauge Wire 200 Amp Fuse Terminals Zip Ties Alternator Boot Kit.
Wiring the alternator for Fords 302-cubic-inch engine is a fairly simple task particularly when compared to the alternators used on other engine designs perhaps because the 302 was created in the 1960s and did not require much wiring to begin with.
1-8 of 8 Results. There is a positive wire that goes to a special 2 ring connector that attaches to BOTH terminals on the solenoid against the firewall. How to Identify Your Ford 3G 4G and 6G Series Alternator. A number of posts on the back of the alternator are used to.


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Before we really get started, I want to say that I was actually really nervous to accept this press sample packet from Color4Nails. When you think of bloggers who stamp… my name will not come up. Do you remember the last time I showed off stamping? Yeah, me neither. I decided to do it though, and I’m glad I did. So here is an amateur stampers review of the Color4Nails X Celestial Holographic Stamping Polish!
So we have 5 holographic stamping polishes to work with here. I decided to do each color over black and each color over white… and then I actually used them on their own as normal polish. These are fairly versatile, which is always good for any polish purchase. Makes you feel like your buck stretched further!
Okay, so we’re gonna jump right in. I used my trusty Konad Stamper and a Bundlemonster plate I picked up somewhere. I didn’t want to get too fancy, but I wanted a full nail image to really test these babies.
As always, you can use my affiliate code CSant10 to save 10% on your order!
Azure is a holographic azure blue.
(Sorry, I apparently didn’t clean all the yellow off the plate for this one!)
Blush is a medium blush pink holographic.
Orchid is a medium cool toned purple holographic. This one has one of the stronger holographic effect of the set.
Poppy is a medium cool toned red holographic. Another stronger holographic shade and my favorite of the group.
Zinnia is a medium golden yellow holographic. Another strong holo effect shade, but not quite as strong as Orchid and Poppy.
Now the full manicures!
Color4Nails X Celestial Holographic Stamping Polish Overview
My initial impression when opening the package? “OMG what did I agree to?!” HOWEVER – once I got started, they were so easy and I picked up the images super easy and whipped right though the stamping. They don’t dry super fast, so I had a bit of time to calm myself and roll the image onto my nails. I like that there are softer shades (Blush and Zinnia) and bolder colors (Orchid, Azure and Poppy) They showed up really nicely over white, and while the main color can be harder to see over black – you can still see a sparkling image.
As an incredibly inexperienced stamper – I feel like these are good to have for practicing because it made me feel like less of a stamping failure. I kind of felt accomplished when I was done because I did it on the first try for each stamp. That’s right… first time. Bam. I win.
Of course if you like the color but aren’t sure if you will stamp or want to get into stamping – they work great as a solid polish as well. Azure applies a little streaky, but overall not bad for the rest.
Of course these 5 holo shades are additions to the C4N & Celestial stamping line, so there are more shades if you wanted to snag some more.
Where To Buy: Color4Nails Website
Release Date: July 21st, 2017 at 5pm PST
Discount Code: Use the code CSant10 at checkout for 10% off
So what do you think? Will you be picking a few of these up?

domain: artistic


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NNDKP has successfully finalized the two successive arbitration cases related to the design and execution of one of the four sections of the Sebes-Turda motorway.
On April 12, 2023, The Legal 500 has launched the 2023 edition of its EMEA rankings. The results of the research conducted among law firms active in Europe reconfirm NNDKP’s position as a leading business law firm in Romania.
NNDKP successfully assisted and represented companies part of Efacec group, a supplier of solutions with presence in the energy, mobility and environment value chain, before the Court of International Commercial Arbitration attached to the Chamber of Commerce and Industry of Romania against Brăila County, a local administrative authority from Romania.
NNDKP received the award „Best Firm of the Year” during the 11th edition of the Romanian Top Lawyers Awards Gala, which recognizes lawyers active in various business law areas for their professional achievements throughout 2020, event organized by Finmedia and Piata Financiara.
Nestor Nestor Diculescu Kingston Petersen announced today the promotion of six lawyers to partnership, in one of the most important rounds of promotions within the firm in recent years. This step is part of NNDKP’s strategy of continuously consolidating its position as a leader of the Romanian business law market.
Representatives of the academic environment, professional organizations, practitioners and representatives of public institutions met during the second edition of the international conference “New Perspectives in Construction Law” organized by the Romanian Construction Law Association in partnership with the Bucharest Academy for Economic Studies.
Nestor Nestor Diculescu Kingston Petersen (NNDKP) announced today that Valentin Voinescu was promoted to partner in the banking and finance department.

domain: law


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Michigan’s Grossest Event Now Has An Heir To The Throne
This 4th of July weekend was a time to get some much needed sun, relax a little and most of all unwind a little bit from the stresses of the year. It's also important to remember that Covid-19 is still real and still out there, and social distancing is still very important. Well it seems that people just figured that because they were on vacation, Covid was too. Huge lake parties took place over the weekend which showed little to no mask wearing or social distancing.
The king of all nasty events, Jobbie Nooner, which took place a few weekends ago saw thousands of people setting the trend. This past weekend, huge parties were captured with shoulder-to-shoulder, non-mask wearing fun that I'm sure is gonna end great. One of the biggest parties took place in Cass County which featured a "petri dish" of possible Covid-19 carriers partying like sardines inside a can at Diamond Lake. The following tweet was sent out and man, does this look like a mess.
This is exactly why we can't have nice things. If even one person in this mosh pit of mindlessness has Covid-19, they had the potential to spread it to thousands of other people. Do people not understand the way viruses work? That's only considering just ONE person has it. Then these infected people are gonna go home and unknowingly infect and endanger the life of others. Nothing is going to be safe to do unless we finally put our pride and selfish wants aside and SOCIALLY DISTANCE.
MORE: Things We Took For Granted Before COVID-19


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Part 21 of a series
The fall of 1918 was a very difficult time in history.
Not only was it the waning months of World War I, but the deadly pandemic known as the Spanish influenza virtually paralyzed cities and towns in Massachusetts.
Regardless of the size of the community, each suffered through the months of September, October and November with churches, schools and theaters closed and all social activities grounding to a halt.
The town of Barre was no different and, sadly, several soldiers from that community were also claimed by the influenza outbreak or other illnesses while serving in war time.
Research historian Lucy Allen of the Barre Historical Society prepared a large manuscript, “The 1918 Influenza Epidemic in Barre, Massachusetts: How One Town Fought Back,” and shared some of the information that went into this column.
With only one doctor left in town to treat hundreds of sick citizens, the local chapter of the Red Cross and Barre’s Board of Health rented the Hotel Barre and ran an emergency center out of it. In addition, a military tent hospital was set up in a field opposite Stetson School under the direction of Lt. Col. William A. Brooks, MD, chief surgeon of the Massachusetts State Guard.
In Barre, the pandemic was the worst tragedy in terms of lives lost in the town’s history, resulting in 22 deaths. Nearly 900 people, or 26 percent of the population, were afflicted.
By early November, schools were allowed to reopen, and a week later the war came to an end.
However, not before four more soldiers from the town of Barre died due to illness.
This is part 21 of our series commemorating A Century of World War I on the local scene, with the third segment on the town of Barre’s contribution to the war.
Allan Frederick Marsh
Died Jan. 8, 1918
Born in Barre on Dec. 31, 1891, the son of Frederick H. and Minnie M. (Cleveland) Marsh, Allan Frederick Marsh was the lone Barre native to die while in the service during World War I.
His father died when Allan was just 2 years of age and he lived with his maternal grandparents on their farm in Barre, where he worked. He entered the Army on Sept. 21, 1917, with the 101st Depot Brigade, and later transferred to Company L, 328th Infantry, 82nd Division.
He was stricken ill with a disease and died at the age of 26 on Jan. 8, 1918, at Camp Gordon, Ga.
John R. Moore
Died, March 6, 1918
John Russell Moore was born in June of 1890, the son of John and Mary (McAdam) Moore of Peters, Prince Edward Island, Canada. He relocated to East Dedham, Mass., and married the former Annie E. Chapman in 1916, and they had a son, John Russell Jr.
In June of 1917, he took a job as a farm laborer on the George H. Ellis Farm on Wauwinet Road in Barre.
Moore entered the Army as part of the Camp Devens Replacement Draft on Oct. 7, 1917, with the 151st Depot Brigade.
He was stricken ill and died at the age of 27 at Post Hospital at Camp Merritt, N.J., on March 6, 1918.
Samuel Robert Daunt
Died, Sept. 30, 1918
A native of nearby Hardwick, Samuel Robert Daunt was born on Dec. 15, 1895, the last-born of 11 children to William and Mary (Sugrue) Daunt. He spent most of his life in Barre as his family owned a farm near the Hardwick town line.
He entered the service in the Army on Aug. 29, 1918, with 24th Company, 6th Training Battalion, with the 151st Depot Brigade, and was sent to then-Camp Devens in Ayer. Unfortunately, this was when the state was in the midst of the deadly influenza pandemic that affected many of the military personnel stationed there and claimed the lives of nearly 800 soldiers.
A little more than a month after he arrived at Camp Devens, Private Daunt contracted lobar pneumonia and died nine days later on Sept. 30, 1918, at the age of 22. He was buried in St. Joseph’s Cemetery in Barre and left seven siblings: Timothy, John, Cornelius, James, William and Marion, all of Hardwick, and Joseph of Beverly.
Daunt was also the great-uncle of former state Rep. Stephen Brewer of Barre.
Robert Jay Clapp
Died, Oct. 3, 1918
Born on July 13, 1892, in South Deerfield, Robert Jay Clapp was the son of Clarence G. and Susie E. (Coates) Clapp. He moved with his family to Barre around 1916 when his father became the superintendent of the Killingly Farm, owned by Col. William Gaston.
Clapp got a job working as a carpenter and enlisted in the service on Dec. 13, 1917, just two weeks before getting married to Ida M. Bacon of Barre.
He was assigned to the naval training station in Charleston, S.C., on April 11, 1918, then on June 1 transferred to the office of superintendent, construction of aircraft, in Buffalo, N.Y. On Aug. 20, he transferred to the receiving ship in Philadelphia.
On Oct. 2, his bride received a telegram informing her that Clapp had been stricken ill with the influenza. While she left to be at his side, he died the next day on Oct. 3, 1918, at the age of 26, at Headquarters North Bombing Squadron in Philadelphia.
He is buried in Green River Cemetery, Greenfield.
Next week: The war comes to an end – or does it?
Comments and suggestions for The Gardner Scene can be sent to Mike Richard at firstname.lastname@example.org or in writing to Mike Richard, 92 Boardley Road, Sandwich, MA 02563.
Barre soldiers who died in the Great War, Part 3
Part 21 of a series

domain: library


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I thought we’d seen the back of electronic drum kits with the demise of Spandau Ballet and their ilk in the 1980s. But they’re back – and this time they’re actually like real drums.
Well, the Traps E400 kit is anyway. Designed by drummers rather than technicians, the E400 kit includes two cymbals, a hi-hat, three toms, a snare drum, bass drum and the stool, all offering the look and feel of a real set of drums, but without the bulk and with one very notable addition – you can plug in a pair of headphones for some silent drumming practice. Which is good for everyone, especially your long-suffering neighbours.
You can pick up the Trap E400 for £450.
Trap drums (via Electric Roulette)
Puzzle your groupies with ThinkGeek’s Air Musician Virtual Guitar watch
Eat up some hardcore riffs with a custom Pac-Man guitar
YouTube Hits: Electric guitar with built-in laptop

domain: hobby


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LOS ANGELES, April 8, 2020 - Open Access BPO was recently named a top global content moderation solutions provider in a study published by market insights firm QY Research.
The recent Global Content Moderation Solutions Market Report, History and Forecast 2015-2026 evaluated the content moderation industry, highlighting the top firms providing the service, with Open Access BPO included in the top 5 notable companies.
Content moderation is the process of monitoring and filtering content submitted to a company’s online platforms. It is an essential component of online business strategies that ensures effective digital marketing, branding, and reputation management.
This is not the first time the research company acknowledged Open Access BPO. Their reports published in September and October last year also recognized the outsourcing firm as a key player in the global content moderation industry.
QY Research considers several factors affecting the sector for these studies. These include government policy, market environment, historical data, technological innovations, and future technologies, among others.
This year’s edition, however, includes the global impact and challenges brought by COVID-19 as a critical factor. It presents the value of establishing business continuity plans and how organizations respond to potential service delivery disruptions.
Most of Open Access BPO’s facilities are in the Philippines, where the government has enforced a community quarantine that can significantly affect business operations. Despite this, the multilingual outsourcing company’s services remain unaffected.
About OPEN ACCESS BPO
Open Access BPO is a multilingual outsourcing firm headquartered in Las Vegas, Nevada. Since its inception in 2006, it evolved from being a telemarketing company to a full-suite provider of scalable multichannel business solutions.
The company extends its expertise to both growing enterprises and established global brands from its operations facilities in Makati and Davao in the Philippines, Taipei, Taiwan, and Xiamen, China. Its multicultural workforce provides a wide range of outsourcing solutions, including multilingual customer support and content moderation in more than 30 languages.


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Free webcams - Shruti kanwar and rithvik dhanjani dating sites
Not to forget, Ashmit Patel and his fiancée Maheck Chahal celebrated his birthday at the party, with the hosts, who are his close friends. Chloe joined it after its creative director Tanusri Dasgupta stepped down. He has learnt acting from Kishore Namit Kapoot acting lab.MTV Fanaah is an impossible love story and what makes it all the more intriguing is the supernatural element in it. Their choreographers Vibhav and Bhavana were also awarded Rs 5 lakh.
(Also Read: Kunal Jaisingh, Devoleena Bhattacharjee, Karan Wahi; TV celebs list down their New Year resolutions)Check out the pictures…
With a smorgasbord of everything a party animal wants, the celebration was studded with stars of the entertainment industry in full attendance to wish their close friends, Chloe and Aslam, all the very best for their new venture.
They were not even friends but over a period of time they became friends and they found out that there could be more to their friendship.
On Marriage plans he said, "We don't have any plans for the next 2-3 years. I think I am still too young to get married and have quite a few plans before I take the plunge.
He debuted on Television as Jay Khurana in Star One's Pyaar Kii Ye Ek Kahaani, apart from that he has also worked in Bandini.
He came into fame with the role of Arjun in the daily soap Pavitra Rishta.Before coming to this television industry, he was a choreographer and when he was in Dubai for his international movie, city of life he also choreographed movie Dabangg's villain Sonu Sood.He also used to help in his father's business but it did not interest him.The event was also graced by Fashion fame Bollywood diva Mugdha Godse, Gaurav Gera, Deepshikha Nagpal, Urvashi Dholakia, Ijaz Ahmed and others.Arjun Bijlani looked smokin hot in his white shirt and denim.The event was graced by TV celebs and they surely partied hard.Tags: Adult Dating, affair dating, sex dating

domain: entertainment


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Every month, Australian Netflix adds a brand-new batch of TV programs and films to its library. The shows offer non-sports fans something to do while others work on sports betting strategies. The Sun Newspaper just published the results of the fourth test, England vs Australia in which the Aussies got 170-3 on a rainy opening day. Day two of the test is about to start at 11 am, and sports fans can catch the game on Sky Sports Ashes. Sky clients can download the app to watch the game no matter where they go.
Everyone else is planning their watching on Netflix, The Spy starts on the 6th of September, and the creator of Prisoners of War directs the six-part thriller. Sacha Baron Cohen, the British comedian, plays a dramatic role and have never starred in anything quite like this. Cohen will be seen in The Spy as Eli Cohen, the agent that gathered intelligence in the early sixties in Syria. The mission to help his country conquer the war in 1967. The Spy is a character-driven film, and it is based partly on a more modern Middle East history as well as the toll of the missions that took place undercover.
A true story inspires the mini-series Unbelievable; it offers an intertwining tales the one is about a young girl in her teenage years who fail to get the authorities to believe that a home invader sexually assaulted her. The other tale is about the detectives that investigate crimes that might confirm the trail they suspect to a serial rapist. The mini-series is created by Susannah Grant, who got an Oscar nomination for Erin Brockovich. The procedural drama, Unbelievable, doubles the critique of rape investigations by the American police.
Max Brallier and Douglas Holgate is a unique combination when it comes to best seller films, Brallier as an author and Holgate for his novels. The Last Kids on Earth tells the tale of a group of teenagers that battles monster and zombies. The animated version offers a retro inventive pulp tone with a hint of the light-heartedness of the book it is based on. The all-star cast includes Rosario Dawson, Keith David, Bruce Campbell and Mark Hamill.
The excellent line-up for September also includes Criminal, Disenchantment Part Two starting on the 20th of September and Bard of Blood on the 27th of September. The Politician begins on the 27th as well, and the actors include Gwyneth Paltrow and Jessica Lange. Great films this month includes Cloudy with a Chance of Meatballs, The Deep Season Two, Moving Art, Season Three, Hip-Hop Evolution Season Three and Travels with My Father, Season Three.


Sixers hope to use win as springboard
The 76ers liked the feeling after Sunday afternoon's 86-82 home playoff victory over the Miami Heat.
"It's a huge win," said Elton Brand. "We'll hopefully be talking about how big the next (victory) is for us."
The Sixers scored the game's final 10 points, while the Heat and their "Big Three" couldn't convert their final four offensive possessions, to overcome a six-point deficit with 1:35 to go.
The Sixers trail the series, 3-1, with Game 5 set for Wednesday evening in Miami.
While rookie Evan Turner, second-year man Jrue Holiday and Lou Williams delivered late for the Sixers, the Heat's Dwyane Wade (twice), LeBron James and Mario Chalmers were missing for Miami.
Turner (17 points, six rebounds) hit a baseline jumper, then Holiday (10 points) swished a step-back 3-pointer to make it a one-point game.
Williams, who scored 11 of his 17 points in the fourth quarter, sent the near-sellout crowd into a frenzy with his deep 3-ball over Wade.
"They did a good job of cutting Jrue and Evan off from getting into the lane, so I figured a jump shot was going to be our best opportunity," Williams said. "Dwyane Wade gave me a little room and I was able to knock it down."