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What is Collagen?
Collagen is the most plentiful healthy protein in your body, as well as it’s a huge part of your ligaments, skin, bones, teeth, muscular tissues and also tendons. Collagen offers your skin toughness and also strength. It aids the cartilage in your joints continue to be supple. It offers framework to your arteries, keeping them strong and also flexible. It provides your bones framework, also, by serving as ‘reinforcing poles’. Collagen is an impressive building and construction product.
Collagen can be found in numerous forms, however the vast bulk in your body consists of types I, II and III. These types all form relatively lengthy fibers (compared to body cells). Type I collagen is – ounce for ounce – more powerful than steel. Type II collagen is thinner than type I, as well as is utilized in cartilage material all bunched up like springs for shock absorption. Type III is very important for the hollow things in your body– like big capillary, the bowel and also bladder.
It’s important to recognize that the ‘kind’ of collagen is only appropriate when it’s currently a part of your body. When you eat it, your body simply re-makes it right into new kinds.
Collagen is so huge and tough that we can not absorb it ‘as is’ when we consume it. What we can do though, is ‘hydrolyze’ the collagen, which means it’s broken down right into a lot smaller items (‘ peptides’) by water, making it useful by your body. Collagen Facility offers easy-to-digest hydrolyzed collagen peptides.
What are the Conveniences of Collagen Supplements?
Each serving of VitaPost Collagen Complex offers restoring hydrolyzed collagen. Collagen supplements are not only helpful for your skin but additionally for your hair, nails, and also joints. It can assist with joint pain as well as arthritis as well as making you feel extra youthful.
VitaPost Collagen Facility provides natural hydrolyzed collagen that supports your body in the regular repair of harmed skin; supports the skin’s natural firmness and also framework; supports skin tone and also can enhance the noticeable look of great lines as well as creases. Research studies have actually concluded that supplementing with collagen can additionally raise skin hydration.
VitaPost Collagen Complex could have fantastic advantages sustaining the body’s upkeep of the skeletal system, especially in ladies that are undertaking natural hormonal changes. Studies recommend a diet plan supplemented with hydrolyzed collagen can support the upkeep of the bone collagen currently present – indicating much less natural degradation of the bones with age.
Collagen in your cartilage is the mechanical reason that joints don’t just break and also break whenever you leap or run. Supplementing the diet plan with hydrolyzed collagen has been associated with joint advantages for an entire variety of individuals, from age-related joint deterioration, to highly-active professional athletes that press their joints to the limit.
Exactly how to Select a Good Quality Collagen Supplement
This post will certainly help you choose which collagen supplement is best for you.
There are several sorts of collagen supplements on the marketplace today. With a lot of options, it can be tough to know which one is the most effective quality. Below are some actions to comply with when looking for a high quality collagen supplement.
1) Examine how much time the business has stayed in business as well as what their credibility resembles.
2) Check out the ingredients and also make certain they have something that will certainly benefit your needs (i.e., kind 1, kind 2, kind 3).
3) Check if there are any type of fillers or other ingredients that could not be as healthy and balanced as what you intend to take into your body and if so, find one with no fillers or additives.
4) Check out client reviews regarding the item.
What is the difference between hydrolyzed collagen and collagen peptides?
There is no distinction. Collagen healthy proteins are long chains of amino acids. The process of hydrolysis breaks them down into peptides, which are simply shorter chains of amino acids. Collagen supplements are otherwise labeled as “hydrolyzed collagen” or “collagen peptides,” yet they coincide.
That needs collagen supplements?
In my opinion, practically every person might profit. Lots of people don’t eat bones, skin, and also connective cells– the parts of pets which contain collagen. That implies they do not obtain the amino acids (particularly hydroxyproline, glycine, and also proline) that are located in collagen however not much in muscular tissue meat.
Just how much collagen should I take daily?
There is no RDA for collagen, as well as to my knowledge, no researches have actually developed optimal application guidelines. You could require more or less depending upon your nutritional intake. To be risk-free, it’s always an excellent suggestion to adhere to the dose guidelines on your collagen supplement of choice.
Can you take too much collagen peptides?
Numerous points in nature follow a J-shaped contour– way too much or inadequate are both poor. The very same could be real for collagen supplements, yet sadly, there’s no indication of what would certainly make up “too much.” There’s likewise no evidence that collagen poisoning is an issue if you following dosing guidelines.
THE LENGTH OF TIME DOES IT CONSIDER COLLAGEN TO WORK?
It depends what you’re taking collagen to sustain. If you’re taking collagen for muscular tissue development, favorable modifications will begin to occur virtually instantly with your workouts– although you might not see the progress right away.
In studies taking a look at collagen supplements for joint discomfort as well as skin flexibility, individuals experienced visible improvements in about four to eight weeks of everyday supplements.
Like any supplement, collagen isn’t an over night wonder treatment but sticking to a daily supplement regimen will certainly produce the most effective outcomes.
What Is Bovine Collagen?
Bovine collagen comes from cows– preferably grass-fed cows.
There are three various types of collagen: collagen I, II, and also III. Each sort of collagen sustains various parts of the body. In bovine collagen made from hide, you’ll typically locate types I and also III which work in comparable means to sustain skin, bones, muscular tissues, tendons, and also gut health.
If you get a bovine collagen supplement made from cartilage material, connective cells, or bones, this supplement should also include collagen kind II which aids support joint wellness in particular.
What Is Marine Collagen?
Marine collagen contains kind I collagen and is generally sourced from wild caught fish. This type of collagen is exceptional for enhancing sustainability practices since it’s made from fish parts that generally end up in the rubbish.
The terrific aspect of marine collagen is that it’s very easy for the body to procedure as well as absorb.
However, any person on a vegan or strict vegan diet plan can not take collagen supplements because it’s constantly sourced from some type of pet product.
Unlike common gelatin, bovine collagen as well as aquatic collagen do not include any pork-derived items so they are appropriate for anybody on a kosher or halal diet.
Does Collagen Break a Fast?
Yes. Given that collagen is a protein, it quits the autophagy process induced during fasting.
Throughout recurring or long-lasting fasting, autophagy happens to clear the cells of built-up toxins. Collagen or any other sort of healthy protein is a precise no while fasting.

domain: biology


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domain: fashion


Q.: We have a problem with too many bug holes on wall surfaces formed with rubber-lined wall forms. Are there ways to achieve the same smooth surface we can get with bare medium-density-overlaid plywood wall forms?
A.: We're not sure we know what you mean by "rubber-lined" wall forms. Are the forms lined with rubber sheets or mats as described in Formwork for Concrete, published by the American Concrete Institute? Or are you referring to an elastomeric form liner?
In any case, rubber or elastomeric liners are more impervious than MDO plywood and could produce more bug holes if all other conditions were equal. Because it's more pervious, an MDO form absorbs water and permits the passage of air and water from the concrete, thus reducing the size and number of bug holes.
Form-surface absorbency also affects the thickness of the layer of form-release agent. A rubber or elastomeric surface, which is impermeable, won't absorb any form-release agent; an MDO surface, which is semi-pervious, will absorb some. So if you apply the same amount of form-release agent to both surfaces, a thicker coating will result on the rubber surface. Thick layers of release agent increase bug hole size and number. Ask the rubber-liner manufacturers to recommend a release-agent type and application rate.
It's also possible that the rubber surface is rougher than the MDO surface, making it easier for bubbles to cling to the surface. And if the rubber liner is installed to impart texture or pattern to the concrete, as is often the case, the surface area of the liner may be two to three times that of a flat form, requiring significantly more vibration to achieve a satisfactory surface.


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Monday, December 21, 2015
Last Week of Advent
We have reached the last week of Advent and have only four days left to prepare out hearts to receive Jesus anew with more fervor and love. Every year, we grow in our capacity to love. We have more to be grateful about and more to rejoice about as we grow older. I am talking about our growth in our interior life. We may lament our decrease in energy or mobility, but we are alive and still growing in the things that matter most.
Since this is a special year of Mercy, let us be merciful and take all into our hearts to help with our prayer, but let us realize that all the suffering in this world is not able to deprive us of gratitude and joy for the many gifts we receive daily. Mary will help us to grow in love and mercy.
“At Christmas,” Pope Francis concluded, “God gives us all of Himself by giving His one and only Son, who is all his joy – and only with the heart of Mary, the humble and poor daughter of Zion, become the Mother of the Son of the Most High, that we can rejoice and be glad for the great gift of God and for His unpredictable surprise: may she help us to perceive the wonder, these three wonders: the other, history and the Church; so let it be with the birth of Jesus – the gift of gifts – the undeserved gift that brings us salvation, that it might also make us feel this wonder in meeting Jesus. We cannot have this wonder, however, we cannot meet Jesus, if we do not meet Him in the other, in history and in the Church.”
(from Vatican Radio)

domain: christianity


DISCLAIMER The images may not contain an accurate depiction of the specifications. For spec details, please refer to the spec sheet.
The legendary Ultravox was born out of obsessively pursuing ‘ultimate ride quality’, tuning the geometry and materials. Closing the gap between man and machine, it presents otherworldly handling, greater stiffness and magic-carpet-ride compliance.
The frame that defines our history – the latest edition of the Ultravox still features world-beating handling with UCI World Tour race-winning pedigree. Stiff yet compliant, precise yet stable, it aims squarely at the Holy Grail of ride quality. Over the years we’ve refined our carbon fibre layup and combinations. Once you ride it, you’ll know, this a special bike, suited for all conditions.
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FRAME Ultravox frame, Full Toray T900 Carbon Fiber, inside frame cable routing, tapered headtube, PF30 System, for Rim brake
FORK Ultravox fork, Full Toray T800 Carbon Fiber, for Rim brake


2008 Mazda Mazda3 i Touring 4dr Sedan (2.0L 4cyl 4A)
I bought my 3 a few weeks ago and do mostly highway driving. Although the fuel economy is not up to par with Honda, it does better than my previous auto. Road noise is a bit loud over 70MPH, but the car has super handling.The responsiveness and handling makes you feel connected to the road. A definite best-buy for its class. Very Pleased. 2.0L is great, but 2.3L is better, if you have the extra $1000-$1500
Handling. Handling. Handling. Handling. Peppiness and steering responsiveness. Excellent Interior, HUGE glove box and trunk. Powerful A/C for those texas-hot January days. :P
Bit better gas mileage, more rear leg room (Kinda small if you're over 6ft) Brighter instrument panel.
† Edmunds.com received the highest numerical score in the proprietary J.D. Power 2014 Third-Party Automotive Website Evaluation Study℠. Results based on responses from 3,381 responses, measuring 14 companies and measures third-party automotive website usefulness among new and used vehicle shoppers. Proprietary study results are based on experiences and perceptions of owners surveyed from January 2014. Your experiences may vary. Visit jdpower.com.


THICKNESS INCONSISTENCY OF A SILICON WAFER
MEASURING THE WARPAGE OF A PCB
MEASUREMENTS OF VALVE STROKE
MEASURING THE THICKNESS / WIDTH OF A STEEL PLATE
With 6 different types of sensor heads, high-precision measurement is possible at distances up to 1 m.
The ABLE function, along with newly developed measurement algorithms, enables measurement of diffuse, transparent, or translucent targets.
Enjoy both high accuracy and sampling speed, two important aspects with laser displacement sensors.
This sensor utilises laser triangulation to balance best-in-class speed and accuracy to provide excellent performance for a wide range of applications.
Introducing a new high-performance head for the IL Series Stable performance for the most demanding detection
The Scale Shot System in the GT2 Series improves upon the technology of conventional contact sensors and is now concentrated into a pencil-type sensor head.


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Photonics Buyers' Guide > Infrared Scanners
Electro-Optical Products Corp. - Fresh Meadows, NY
(14 companies)Infrared Scanners
An infrared scanner is an optical system used to collect infrared energy from a scene using scanning optics with a point or line detector, as compared with a fixed optical system with a full two-dimensional detector array.
Electro-Optical Products Corp. is a manufacturer and supplier of high quality, low cost and long life components used with light, plasma, X-Ray and lasers. Our products offer breakthrough, practical, energy-saving solutions for OEM customers. We offer experience, non-stop innovation and superior...
- Manufacture Stock
- Manufacture Custom
- Exergen Corp. - Watertown, MA
- Fluke Corp., Fluke Process Instruments - Santa Cruz, CA
- HGH Infrared Systems - Igny, France
- Iscon Imaging - Woburn, MA
- L-3 Sonoma EO Inc., Div. of L-3 Communications - Santa Rosa, CA
- NDC Technologies, A Spectris Co., Web Solutions - Irwindale, CA
- Optical Energy Technologies Inc. - Stamford, CT
- Pyrometer Instrument Co., Inc. - Windsor, NJ
- Raytek Corp., Div. of Fluke Corp., Automation Products - Santa Cruz, CA
- Raytek GmbH, A Fluke Co. - Berlin, Germany
- Teletherm Infrared Systems/Research, Div. of TG3 Infrared Systems LLC, Medical Thermal Imaging/Diagnostics - Hendersonville, NC
- Thermoteknix Systems Ltd. - Cambridge, England
- Xyntek, Inc. - Yardley, PA
- infrared scanner An optical system used to collect infrared energy from a scene using scanning optics with a point or line detector, as compared with a fixed optical system with a full two-dimensional detector array.
- scanner 1. A device used to trace out an object and build up an image. One of the most common of these types is video scanning. The scanning takes place inside the television tube as electrons, guided by electron optics, sweep linearly across a tube face...
- infrared (IR) The invisible portion of the electromagnetic spectrum that lies between about 0.75 and 1000 µm. Radiation in the near-infrared produces a sensation of heat.

domain: physics


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domain: artistic


When the School District of Philadelphia had an interested buyer for one of the 22 schools it needed to close in 2013, it presented an opportunity for innovation, collaboration, economic growth, and community revitalization. Ballard Spahr provided a comprehensive approach to the sophisticated structuring of the project and the broad range of legal competencies required to close the deal.
The Drexel University City Development, a partnership between Drexel University and Wexford Science + Technology, a BioMed Realty company, will transform the 14-acre parcel and the West Philadelphia neighborhood where it sits. This 2.7-million-square-foot mixed-use project is a unique combination of research and lab facilities, office space for technology companies, high-rise and low-rise residential, national and independent retail space, recreational areas, and a new K-8 public school.
With the influx of technology companies to the area, the project’s residential units—from townhouse-style apartments to a multifamily high-rise—should be readily occupied, drawing residents to the area and contributing to the long-term prospects of University City’s growing science corridor. The project is expected to generate 4,300 new construction jobs and 5,600 permanent jobs.
“Given the track record of University City in growing jobs in science and technology, the Drexel/Wexford development will bolster the economic vitality of the area,” said Ballard Spahr Real Estate Department Chair Bart I. Mellits, who led the firm’s team in this transaction. “It will make an extraordinary mark, both in generating economic development and in promoting the urban experience in Philadelphia neighborhoods.”


Gender: : Male
Branch: : Mechanical Engineering
City : Aurangabad
i am the student of BE-MECH and want ppt on the above mention topice so pls help me out....
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Int. J. Mol. Sci. 2015, 16, 25323-25337; doi:10.3390/ijms161025323 OPEN ACCESS
International Journal of
Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review
Membranotropic Cell Penetrating Peptides: The Outstanding Journey Annarita Falanga 1, Massimiliano Galdiero 2,3 and Stefania Galdiero 1,2,* 1
Department of Pharmacy, University of Naples “Federico II”, Via Mezzocannone 16, 80134 Naples, Italy; E-Mail: [email protected]
CiRPEB, University of Naples “Federico II”, Via Mezzocannone 16, 80134 Naples, Italy; E-Mail: [email protected]
Department of Experimental Medicine, II University of Naples, Via De Crecchio 7, 80138 Naples, Italy
* Author to whom correspondence should be addressed; E-Mail: [email protected]
; Tel.: +39-081-253-4503; Fax: +39-081-253-4560. Academic Editor: Jagdish Singh Received: 18 September 2015 / Accepted: 20 October 2015 / Published: 23 October 2015
Abstract: The membrane bilayer delimits the interior of individual cells and provides them with the ability to survive and function properly. However, the crossing of cellular membranes constitutes the principal impediment to gaining entry into cells, and the potential therapeutic application of many drugs is predominantly dependent on the development of delivery tools that should take the drug to target cells selectively and efficiently with only minimal toxicity. Cell-penetrating peptides are short and basic peptides are widely used due to their ability to deliver a cargo across the membrane both in vitro and in vivo. It is widely accepted that their uptake mechanism involves mainly the endocytic pathway, the drug is catched inside endosomes and lysosomes, and only a small quantity is able to reach the intracellular target. In this wide-ranging scenario, a fascinating novel hypothesis is that membranotropic peptides that efficiently cross biological membranes, promote lipid-membrane reorganizing processes and cause a local and temporary destabilization and reorganization of the membrane bilayer, may also be able to enter cells circumventing the endosomal entrapment; in particular, by either favoring the escape from the endosome or by direct translocation. This review summarizes current data on membranotropic peptides for drug delivery.
Int. J. Mol. Sci. 2015, 16
Keywords: membranotropic peptides; hydrophobicity; fusion; delivery
1. Introduction The plasma membrane is a highly effective and selective barrier that determines the ability of cells to survive and function properly. However, this barrier also constitutes a primary obstacle for intracellular delivery of theranostics. Notwithstanding their potentiality, a number of novel molecules do not reach the pharmaceutical stage and do not tickle industrial interest because of their low cell membrane permeability; in fact, these molecules should be delivered intracellularly to induce a biological effect. Thus, a key issue to enhance the therapeutic potential of a drug is the development of delivery tools which should take the drug to target cells selectively and efficiently with only minimal toxicity. The blood brain barrier (BBB), is a dynamic interface preventing transport of most drugs from the vasculature into the brain parenchyma  and thus delivering a drug across the BBB is an even more difficult task. Improving the drug cellular uptake represents a great challenge for scientists working in the field of drug development. Over the past few decades, nanotechnology has been successfully exploited in design numerous platforms for theranostics, each presenting its own advantages and disadvantages. In particular, several nanocarriers (polymers, nanoparticles, liposomes, micelles, and dendrimers) have been extensively studied for drug delivery to cells [2–6]. Their delivery is generally dependent on passive accumulation in the pathological regions; thus, the delivery is not specific and healthy tissues are also involved. Recently, extensive literature has described the use of short cationic and/or amphipathic peptides, usually known as cell-penetrating peptides (CPPs), for mediating drug delivery due to their intrinsic ability to enter cells and mediate uptake of a wide range of macromolecular cargoes [7–10]. Thus, CPPs have huge potential in biotechnology, but, in order to achieve this potential, it will be important to understand how they cross biological membranes and localize to specific intracellular compartments. Their main features are low cytotoxicity, ability to internalize into a variety of cell types, dose-dependent efficiency, no restriction with respect to the size or type of cargo, ability to transport covalently or non-covalently conjugated cargoes. Macromolecules are usually transported into the cell by endocytosis  which occurs by multiple mechanisms that essentially fall into two distinct categories: phagocytosis and pinocytosis. Phagocytosis is a complex process involving the uptake of large particles and is usually restricted to specialized mammalian cells. Pinocytosis occurs in all cell types and involves the uptake of smaller particles. It is widely accepted that the main pathway of CPPs mediated uptake is endocytosis, but direct uptake by energy independent pathways have also been reported for specific CPPs. The uptake mechanism of CPPs is not fully understood, but the process seems to vary considerably from peptide to peptide . It is likely that CPPs can enter cells via multiple pathways, including direct penetration of the plasma membrane and endocytic uptake according to the nature of the peptide/cell interaction [13–16]. In order to optimize the nanosystem and produce maximum effect, and enhance intracellular behavior and efficiency of cargo delivery, it is fundamental to understand the uptake mechanism and intracellular trafficking of drug carriers. Although CPPs have been widely used to deliver cargo
Int. J. Mol. Sci. 2015, 16
molecules into cells, their exact uptake mechanism is still an issue and lots of answers are still sought after. It is now evident that the cellular uptake mechanisms depend on each CPP features, the carried molecule, the cell type and the membrane lipid composition. This wide variety of possibilities results in different modes and levels of uptake. 2. CPP Classification CPPs have been categorized according to several criteria. Our classification is based on their hydrophilicity and hydrophobicity and thus on their different interaction with the membrane bilayer. The first group is composed of cationic CPPs. The prototype of this class is represented by the HIV-1 protein TAT . These peptides have a high content of arginine, lysine and histidine residues. The arginine guanidine head group forms hydrogen bonds with the negatively charged phosphates and sulphates on the cell membrane and might lead to internalization under physiological pH conditions. The lysine is a cationic amino acid as the arginine, but it lacks the guanidine head group, and therefore is less effective at penetrating the plasma membrane. Several studies have demonstrated that, for efficient cellular uptake, it is necessary to have at least eight positive charges . The second group is composed of membranotropic and amphipathic peptides, which contain hydrophobic amino acids and present a low net charge. The amphipathicity plays a crucial role in their ability to interact with the membrane bilayer and thus in their mechanism of internalization. Amphipathic CPPs are divided into: primary amphipathic CPPs, secondary amphipathic α-helical CPPs, β-sheet amphipathic CPPs, and proline-rich amphipathic CPPs . These peptides are characterized by the presence of lipophilic and hydrophilic blocks or by the presence of a lipophilic and hydrophobic face that are involved in mediating the peptide translocation across the cell membrane . Viral fusion peptides belong to the group of membranotropic CPPs . This class of peptides will be the object of the present review (a list of examples of peptides belonging to this class is reported in Table 1).
Int. J. Mol. Sci. 2015, 16
25326 Table 1. Examples of membranotropic peptides used in drug delivery.
Name Pep-1 pVEC VT5 C105Y Transportan TP10 MPG gH625 INF CADY GALA
Origin NLS from Simian Virus 40 large antigen and reverse transcriptase of HIV VE-cadherin Synthetic peptide 1-antitrypsin Galanin and mastoparan Galanin and mastoparan A hydrofobic domain from the fusion sequence of HIV gp41 and NLS of SV40 T antigen Glycoprotein gH of HSV type I Influenza HA2 fusion peptide PPTG1 peptide Synthetic peptide
Amino Acid Sequence
LLIILRRRRIRKQAHAHSK DPKGDPKGVTVTVTVTVTGKGDPKPD CSIPPEVKFNKPFVYLI GWTLNSAGYLLGKINLKALAALAKKIL AGYLLGKINLKALAALAKKIL
Primary amphipathic β-sheet amphipathic Primary amphipathic Primary amphipathic

HGLASTLTRWAHYNALIRAF GLFEAIEGFIENGWEGMIDGWYGC GLWRALWRLLRSLWRLLWRA WEAALAEALAEALAEHLAEALAEALEALAA
Secondary amphipathic α-helical Secondary amphipathic α-helical Secondary amphipathic α-helical Secondary amphipathic α-helical

Int. J. Mol. Sci. 2015, 16
3. Membranotropic Peptides Membranotropic peptides are a class of peptides playing a prominent role in biology. Their simultaneous hydrophobic and amphipathic nature determines their high propensity for binding to lipid membranes. To look at the valuable features possessed by membranotropic peptides in more detail, one should start with their physical properties. Membranotropic peptides are characterized by the presence of an unusually high content of alanine and glycine residues and often also prolines. This high content of Ala/Gly determines their peculiar features compared to signal sequences and transmembrane anchors; moreover, they determine the intrinsic conformational flexibility which is typical of membrane interacting peptides. Moreover, membranotropic peptides present a high content of aromatic residues, whose side chains are able to form favourable interactions with phospholipid groups which are located at the membrane interface and thus contribute to the insertion of the peptide into the bilayer . Their cellular uptake is strongly dependent on the secondary structure adopted after interaction with cellular plasma membrane. A key feature of these peptides is amphipathicity . They can be amphipathic in their primary structure or secondary structure. While primary amphipathic peptides present a sequential assembly of hydrophobic and hydrophilic domains separated by a spacer, secondary amphipathic peptides present a secondary structure with hydrophobic and hydrophilic residues located on opposite sides. The two faces of secondary amphipathic peptides are often characterized by the presence of large and aromatic residues on one face with and small residues such as Ala/Gly on the other face. This distribution of amino acid residues enhances the interaction and insertion within the membrane bilayer . Conformational polymorphism is also relevant for determining the uptake mechanism, in fact, the ability to change from random to α or β conformations following membrane interaction is a peculiar trait of this class of peptides . Several structural models describing interactions between peptides and membranes have emerged in recent years, which include membrane permeabilization through the formation of stable pores (such as barrel-stave and toroidal pore models) or micellization on a detergent-like way (carpet model) . The main differences between these models are the lipid structure around the pores and their stability. In the barrel-stave model, peptide helices form well-defined and stable bundles, which can serve as a pore. In the toroidal-pore model, the lipids create a pore covered with peptides in different orientations; as a consequence, these pores are less stable. In the carpet model, peptides accumulate, adsorb and span the bilayer surface until its integrity is violated and transient holes are formed allowing additional peptides to penetrate the membrane; as a consequence, the membrane disintegrates in a dispersive-like manner rather than channel formation, and peptides do not necessarily insert into the hydrophobic membrane core. Peptide-membrane interactions are complex and diverse phenomena and according to peptide composition, charge, and structure, different peptides may employ different interaction mechanisms with the membrane. Membranotropic CPPs’ strong affinity for the membrane bilayer is dominated by hydrophobic interactions. Thus, they penetrate deeper into the hydrophobic core compared to cationic CPPs but do not span the bilayer in a pore-like manner. On the contrary, they tend to self-associate at the interface between the membrane and the aqueous compartments which could be relevant for direct translocation. As a matter of fact, an inverted micelle model has been proposed for many membranotropic CPPs. This model cannot be applied for explaining the uptake of cationic CPPs which do not contain the hydrophobic amino acids necessary for the translocation
Int. J. Mol. Sci. 2015, 16
process. In addition to the inverted micelles model, direct translocation can be achieved also via transient pore formation or carpet-like perturbations. Thus, direct translocation involves stable or transient destabilization of the membrane bilayer associated with folding of the peptide in the lipid membrane. In general, the uptake mechanism may also depend on the CPP concentration. Cationic CPP uptake is achieved by endocytosis at low peptide concentrations but may switch to direct uptake above a certain threshold ; moreover, primary hydrophobic CPP direct penetration is more probable at high concentrations. On the contrary, membranotropic CPPs direct penetration likely takes place at both high and low CPP concentrations. Although the concentration threshold for direct penetration varies according to the different CPP, different cell lines, the presence and type of cargo and mainly the mechanism of interaction with the membrane bilayer. It is widely accepted that the interaction of each CPP with cellular membranes determines their uptake efficiency, but when they carry a cargo inside cells, several factors have to be taken into consideration, spanning from the nature of the conjugated cargo (type, size, charge) to differences in the properties of the CPP (length, charge, hydrophobicity, secondary structure) as well as the cells lines under investigation and the concentrations of both the CPP and the cargo. Depending on these factors several internalization routes may act simultaneously. Nevertheless, cationic CPPs transport their cargo inside cells essentially using endocytosis. Thus, the cargo needs to escape from the endosomal vesicle in order to exert its action. If the cargo remains entrapped into the endosomes, it will end into lysosomes where degradation processes take place which abolish the biological effects of the cargo. On the contrary, membranotropic CPPs uptake of mechanisms mainly involve direct penetration of the plasma membrane and, consequently, immediate bioavailability of the cargo. In fact, hydrophobic peptides that partition into membranes are able to efficiently interact with membranes and enter cells which also includes the crossing of endothelial layers in vivo [21,38]. Moreover, these peptides are able to efficiently cross biological membranes, promote lipid-membrane reorganizing processes (fusion or pore formation) and determine a local and temporary membrane destabilization with subsequent reorganization [39,40]. Moreover, they can circumvent the endosomal entrapment both favouring the escape from the endosome and translocating a cargo through the plasma membrane directly into the cell (Figure 1). Modifying the internalization mechanism of a cargo will also modify the toxicity of the internalized drug and may be involved in the overcoming of drug resistance problems.
Figure 1. Mechanism of internalization of gH625 coupled to a cargo. In yellow are reported membrane bilayers, in green the cargo and in black the CPP.
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4. Examples of Membranotropic CPPs CADY is a 20 residue peptide, which contains both aromatic tryptophan residues and cationic residues. It assumes an amphipathic helical conformation when in the bilayer, with charged residues on one side and Trp on the other. The helical conformation is involved in the interactions with the cell membrane and in the mechanism of cell penetration. CADY has been used to enhance cellular uptake of siRNA , and its internalization is barely affected by the use of inhibitors of the endosomal pathway. MPG is a 27 amino acid peptide derived from the hydrophobic fusion domain of HIV gp41 which is thought to be responsible of cellular entry and the hydrophilic nuclear import sequence of SV40 T antigen which binds the cargo and also facilitates entry into the nucleus . The glycine-rich HIV fusion peptide is essential for membrane fusion activity while the NLS of the SV40 large T antigen improves the nuclear targeting [41,42]. In vitro studies have shown that MPG can deliver both siRNA and DNA after just 1 h . The hydrophobic domain is critical for insertion into membranes. MPG cellular uptake exploits different routes; nevertheless, the major cell translocation mechanism is independent of the endosomal pathway and temporarily involves membrane disorganization and folding into β-structures within the membrane bilayer without any associated leakage or toxicity; all these fenomena facilitate insertion into the membrane and initiation of translocation. Pep-1 is partially derived from MPG; in fact, it conserves the C-terminal hydrophilic domain corresponding to the NLS of SV40 large T antigen; the hydrophobic region instead corresponds to a tryptophan-rich sequence (KETWWETWWTE) derived from the HIV-1 reverse transcriptase [22,23]. Pep-1 is able to efficiently deliver a variety of cargos into several cell lines in a fully active form. The strong interaction with the lipid bilayer, causes local perturbation and allows the peptide to cross the membrane by a physical mediated mechanism promoted by the transmembrane potential and not involving pore formation [22,44,45]. Pep-1 interaction with membranes is key for its cellular uptake and is correlated to a conformational change from random coil in water to α-helix in membrane. The hydrophobic domain is involved in this conformational change which as a consequence allows its easy insertion into the membrane. The peptide is able to transiently modify the cell-membrane organization without causing any leakage or toxicity, and thus smoothing insertion into the membrane and initiation of the translocation process. The ability to directly interact with lipids also limits the association with proteoglycans at the cell surface, accelerating cellular entry and reducing the extent of internalization through the endosomal pathway. This mechanism does not completely exclude the endocytic internalization but the length of time required for the translocation is considerably lower than entry by the endocytic pathway. Therefore, when both mechanisms are effective, the nonendocytic pathway is prevailing. C105Y is a synthetic peptide based on the amino acid sequence of a1-antitrypsin and was shown to enter the cytoplasm, nucleus, and nucleolus of live cells very rapidly . C105Y uptake and internalization does not occur through known endocytic pathways. C105Y attached to polyK was used to condense plasmid DNA and allowed a 100-fold increase in gene expression compared to polyK-DNA complexes that did not contain C105Y. This complex was also able to increase gene expression in vivo. Herpes Simplex Virus Type 1 (HSV-1) Protein VP22  is a major component of the tegument and has been reported to traffic between cells ; its C-terminal 40 amino acid domain has been
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shown to be responsible for the transduction property of the whole protein and its was demonstrated to be able to mediate the delivery of DNA and RNA oligonucleotides into cells [48,49]. The 4-kDa peptide called “gamma” (γ) derived from the insect Flock House virus (FHV)  contains an N terminal region that is able to alter membrane structure and increase bilayer permeability . In fact, biophysical studies have shown that this domain presents membranotropic features and is able to strongly bind fluid phase lipid bilayers increasing transmembrane permeability. Its activity is similar to that of known membrane active peptides such as melittin and alamethicin ; thus, peptide-triggered disruption of the endosomal membrane may represent a premise to viral uncoating in the host cytoplasm. Comparisons with the TAT peptide showed that the FHV peptide was able to internalise with a higher efficiency . Transportan and TP10 are synthetic peptides derived from the N-terminal domain of the neuropeptide galanin linked through a lysine residue to mastoparan. It translocates across the membrane bilayer and has been used for the transfer of several cargoes. The internalization is not correlated to the presence of a receptor, energy and temperature . Moreover, it could involve both by endocytosis and direct translocation. Structural analysis shows that it adopts a helical conformation in the presence of the membrane bilayer. pVEC is derived from the murine vascular endothelial-cadherin protein and has proved to be able to translocate into different cell lines. Direct translocation has been attributed to the presence of N-terminal hydrophobic residues . INF  and GALA  have been shown to increase the transfection efficiencies; they are α-helical peptides with pH-dependent fusogenic and endosomolytic activities able to enhance lysosomal degradation before the contents of the endosomes are delivered to lysosomes. VT5 is a synthetic water soluble amphipathic 26-mer β-sheet peptide which was shown to be able to enhance internalization into endothelial cells; the mechanism of entry of VT5 into the cells has not been revealed yet, but it was shown to be energy, temperature and pH dependent . 5. gH625, a Delivery Sequence Derived from Herpes Simplex Virus Type I Among membranotropic peptides with a tendency to membrane binding and a high interfacial hydrophobicity or amphipathicity, those derived from enveloped virus glycoproteins are particularly challenging because they can physically interfere with the hydrophobic surfaces located on membranes and/or fusion proteins during the enveloped virus entry and are, thus, involved both in fusion and entry. Moreover, CPPs present in viruses that can infect many different hosts may have a wide applicability. The high content of aromatic residues is probably associated to the overcoming of the energy cost of peptide bond partitioning into membranes and determine the insertion of the peptide into just one leaflet of the bilayer . This asymmetric insertion into only one membrane monolayer causes the formation of bulges that stick out of the membrane and ease contacts between fusing bilayers . The entry of viruses involves several membrane reorganization processes such as transient permeabilization of the bilayer, which are similar to the ones involved in delivery across cellular membranes. A milestone in understanding the role of hydrophobic viral peptides is figured out by the sequence “gH625” derived from glycoprotein H of Herpes simplex virus type I, developed in our laboratory .
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HSV fusion proteins contain several membranotropic sequences with the ability to bind and disrupt model membranes [56–66], which are involved in the local destabilization of the membrane bilayer which determines the fusion of the viral and host cell membranes [58,60,66,67]. gH625 corresponds to the HSV-1 region with the highest fusion capability which was initially identified using the Wimley-White interfacial hydrophobicity scale (WWIH) and subsequent studies demonstrated the numerous use of this sequence including membrane fusion, viral inhibition and drug delivery [21,68,69]. gH625 is a membrane-perturbing domain, containing key residues for interacting and destabilizing biological membranes [64,66,70]. In fact, it is rich in hydrophobic residues including glycines, leucines, alanines, and aromatic residues such as tryptophan and tyrosines, which are known to be located preferentially at the membrane interface. The hydrophobic domain is fundamental for its insertion into the membrane and is involved in the early stages of membrane perturbation. The peptide gH625 is able to interact with model membranes, to insert into the bilayer from its N-terminal side; moreover, it has a tryptophan residue buried inside the bilayer, and adopts an amphiphatic helical conformation. The amphipathic helices would allow the peptide to enter the membrane, and trigger local fusion of the membrane leaflets, transient pore formation, cracks and membrane fusion [60,63–65]. The initial interactions with the membrane and the oligomerization process is favoured by the presence of the histidine residue at the N-terminus of the native sequence, which strongly increases the fusion activity . In fact, the presence of any other residue at the N-terminus impaired the fusion ability of the peptide (data not published). The hydrophobic and amphipathic profile of gH625 provides the necessary distinctive features for the interaction with membrane lipids and the formation of a transient helical structure that temporarily affects membrane organization, thereby facilitating insertion into the membrane and translocation [29,71]. gH625 has been shown to be able to directly translocate across the membrane bilayer and to transport into the cytosol several cargoes [21,29,38,39,71–79] (Figure 1). gH625-QDs internalization was shown to be highly enhanced and to involve the endocytic pathway only to a minor extent . Liposomes armed with gH625 on their external surface and loaded with doxorubicin (DOXO)  or mitoxantrone (MTX) , were shown to penetrate inside cells and influence the uptake mechanism of liposomes and the intracellular distribution and release of the drug. Moreover, the presence of gH625 was shown to determine an increased uptake also in DOXO resistant cells . Poly(amide)-based dendrimers coupled to gH625 on the termini allowed the enhanced translocation of the conjugate [72–74]. A non-active translocation mechanism was shown to be involved in the internalization of peptide-functionalized dendrimers . gH625 was also used to enhance the uptake of NPs by brain endothelial cells , and it decreased NP intracellular accumulation as large aggregates and enhanced the NP blood brain barrier crossing. Recently, we evaluated the ability of gH625 to cross the BBB in vivo . The peptide was administered in vivo to rats, and its presence in the liver and in the brain was analysed. Within 3.5 h from its i.v. administration, the peptide was found beyond the BBB in proximity of cell neurites. Moreover, it did not show toxic effects in vivo. In fact, it did not influence the brain maximal oxidative capacity and mitochondrial respiration rate. Our data further support the possible use of gH625 as a novel nano-carrier system for drug delivery to the central nervous system.
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6. Conclusions Synthetic peptides are particularly attractive candidate nanomaterials to be developed as delivery vectors since they have the flexibility to incorporate different functionalities. In fact, they can overcome extra and intracellular barriers, they can achieve tissue and cell type specificity, and they can be coupled covalently and non-covalently to a variety of cargoes and they generally show low cytotoxicity. Membranotropic CPPs represent a challenge for drug delivery as they can translocate directly across membranes. Direct translocation could be especially advantageous because they would be immediately available in the cytosol and the risk of endosomal entrapment and degradation would be eliminated. A further advantage in favour of membranotropic peptides is the fact that modifying the internalization mechanism and avoiding the endocytic pathway determines a reduction of toxicity and probably helps in overcoming drug resistance problems. Despite many studies on CPPs, the mechanism by which different CPP enter cells has not been exactly determined. Unfortunately, there is no specific biological or biophysical method that could provide a comprehensive answer to all questions and, therefore, a combination of different methods and techniques is indispensable . The in vitro and in vivo use of CPPs as drug delivery vectors is, however, limited by the lack of cell specificity; this means that a particular valuable goal in the medicinal field is the creation of a platform functionalized both with CPPs for enhancing uptake and targeting peptides for favouring specificity [82,83]. Although the number of studies devoted to CPPs is increasing, there is still space for improvements regarding the molecular mechanisms that underlie features such as their cellular uptake and membrane translocation, the efficacy in the presence of serum and enhancement of endosomal escape. Understanding all of these points is a necessary requirement to characterize the structural basis for modulation of these peptides and for all researchers involved in the design of novel theranostic systems. Conflicts of Interest The authors declare no conflict of interest. References 1. 2.
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60. Galdiero, S.; Falanga, A.; Vitiello, M.; Browne, H.; Pedone, C.; Galdiero, M. Fusogenic domains in herpes simplex virus type 1 glycoprotein H. J. Biol. Chem. 2005, 280, 28632–28643. 61. Galdiero, S.; Falanga, A.; Vitiello, M.; D’Isanto, M.; Cantisani, M.; Kampanaraki, A.; Benedetti, E.; Browne, H.; Galdiero, M. Peptides containing membrane-interacting motifs inhibit herpes simplex virus type 1 infectivity. Peptides 2008, 29, 1461–1471. 62. Galdiero, S.; Falanga, A.; Vitiello, M.; D’Isanto, M.; Collins, C.; Orrei, V.; Browne, H.; Pedone, C.; Galdiero, M. Evidence for a role of the membrane-proximal region of herpes simplex virus type 1 glycoprotein H in membrane fusion and virus inhibition. Chembiochem 2007, 8, 885–895. 63. Galdiero, S.; Falanga, A.; Vitiello, M.; Raiola, L.; Fattorusso, R.; Browne, H.; Pedone, C.; Isernia, C.; Galdiero, M. Analysis of a membrane interacting region of herpes simplex virus type 1 glycoprotein H. J. Biol. Chem. 2008, 283, 29993–30009. 64. Galdiero, S.; Falanga, A.; Vitiello, M.; Raiola, L.; Russo, L.; Pedone, C.; Isernia, C.; Galdiero, M. The presence of a single N-terminal histidine residue enhances the fusogenic properties of a membranotropic peptide derived from herpes simplex virus type 1 glycoprotein H. J. Biol. Chem. 2010, 285, 17123–17136. 65. Galdiero, S.; Russo, L.; Falanga, A.; Cantisani, M.; Vitiello, M.; Fattorusso, R.; Malgieri, G.; Galdiero, M.; Isernia, C. Structure and orientation of the gH625-644 membrane interacting region of herpes simplex virus type 1 in a membrane mimetic system. Biochemistry 2012, 51, 3121–3128. 66. Galdiero, S.; Vitiello, M.; D’Isanto, M.; Falanga, A.; Cantisani, M.; Browne, H.; Pedone, C.; Galdiero, M. The identification and characterization of fusogenic domains in herpes virus glycoprotein B molecules. Chembiochem 2008, 9, 758–767. 67. Akkarawongsa, R.; Pocaro, N.E.; Case, G.; Kolb, A.W.; Brandt, C.R. Multiple peptides homologous to herpes simplex virus type 1 glycoprotein B inhibit viral infection. Antimicrob. Agents Chemother. 2009, 53, 987–996. 68. Galdiero, S.; Falanga, A.; Tarallo, R.; Russo, L.; Galdiero, E.; Cantisani, M.; Morelli, G.; Galdiero, M. Peptide inhibitors against herpes simplex virus infections. J. Pept. Sci. 2013, 19, 148–158. 69. Vitiello, G.; Falanga, A.; Galdiero, M.; Marsh, D.; Galdiero, S.; D’Errico, G. Lipid composition modulates the interaction of peptides deriving from herpes simplex virus type I glycoproteins B and H with biomembranes. Biochim. Biophys. Acta 2011, 1808, 2517–2526. 70. Vitiello, G.; Falanga, A.; Petruk, A.A.; Merlino, A.; Fragneto, G.; Paduano, L.; Galdiero, S.; D’Errico, G. Fusion of raft-like lipid bilayers operated by a membranotropic domain of the HSV-type I glycoprotein gH occurs through a cholesterol-dependent mechanism. Soft Matter 2015, 11, 3003–3016. 71. Falanga, A.; Vitiello, M.T.; Cantisani, M.; Tarallo, R.; Guarnieri, D.; Mignogna, E.; Netti, P.; Pedone, C.; Galdiero, M.; Galdiero, S. A peptide derived from herpes simplex virus type 1 glycoprotein H: Membrane translocation and applications to the delivery of quantum dots. Nanomedicine 2011, 7, 925–934. 72. Borchmann, D.E.; Tarallo, R.; Avendano, S.; Falanga, A.; Carberry, T.P.; Galdiero, S.; Weck, M. Membranotropic peptide-functionalized poly(lactide)- graft -poly(ethylene glycol) brush copolymers for intracellular delivery. Macromolecules 2015, 48, 942–949.
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73. Carberry, T.P.; Tarallo, R.; Falanga, A.; Finamore, E.; Galdiero, M.; Weck, M.; Galdiero, S. Dendrimer functionalization with a membrane-interacting domain of herpes simplex virus type 1: Towards intracellular delivery. Chemistry 2012, 18, 13678–13685. 74. Falanga, A.; Tarallo, R.; Carberry, T.; Galdiero, M.; Weck, M.; Galdiero, S. Elucidation of the interaction mechanism with liposomes of gH625-peptide functionalized dendrimers. PLoS ONE 2014, 9, e112128. 75. Falanga, A.; Tarallo, R.; Galdiero, E.; Cantisani, M.; Galdiero, M.; Galdiero, S. Review of a viral peptide nanosystem for intracellular delivery. J. Nanophotonics 2013, 7, 071599. 76. Galdiero, S.; Falanga, A.; Cantisani, M.; Vitiello, M.; Morelli, G.; Galdiero, M. Peptide-lipid interactions: Experiments and applications. Int. J. Mol. Sci. 2013, 14, 18758–18789. 77. Smaldone, G.; Falanga, A.; Capasso, D.; Guarnieri, D.; Correale, S.; Galdiero, M.; Netti, P.A.; Zollo, M.; Galdiero, S.; di Gaetano, S.; et al. gH625 is a viral derived peptide for effective delivery of intrinsically disordered proteins. Int. J. Nanomed. 2013, 8, 2555–2565. 78. Tarallo, R.; Accardo, A.; Falanga, A.; Guarnieri, D.; Vitiello, G.; Netti, P.; D’Errico, G.; Morelli, G.; Galdiero, S. Clickable functionalization of liposomes with the gH625 peptide from herpes simplex virus type I for intracellular drug delivery. Chemistry 2011, 17, 12659–12668. 79. Valiante, S.; Falanga, A.; Cigliano, L.; Iachetta, G.; Busiello, R.A.; la Marca, V.; Galdiero, M.; Lombardi, A.; Galdiero, S. Peptide gH625 enters into neuron and astrocyte cell lines and crosses the blood-brain barrier in rats. Int. J. Nanomed. 2015, 10, 1885–1898. 80. Perillo, E.; Allard-Vannier, E.; Falanga, A.; Stiuso, P.; Vitiello, M.T.; Galdiero, M.; Galdiero, S.; Chourpa, I. Quantitative and qualitative effect of gH625 on the nanoliposome-mediated delivery of mitoxantrone anticancer drug to hela cells. Int. J. Pharm. 2015, 488, 59–66. 81. Perillo, E.; Porto, S.; Falanga, A.; Zappavigna, S.; Stiuso, P.; Galdiero, M.; Galdiero, S.; Caraglia, M. Liposome armed with herpes virus-derived gH625 peptide to overcome resistance in lung adenocarcinoma cell lines. J. Biomed. Nanotechnol. 2015, in press. 82. Ringhieri, P.; Diaferia, C.; Galdiero, S.; Palumbo, R.; Morelli, G.; Accardo, A. Liposomal doxorubicin doubly functionalized with CCK8 and R8 peptide sequences for selective intracellular drug delivery. J. Pept. Sci. 2015, 21, 415–425. 83. Sanna, V.; Pala, N.; Sechi, M. Targeted therapy using nanotechnology: Focus on cancer. Int. J. Nanomed. 2014, 9, 467–483. © 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).

domain: chemistry


text:
More than three decades after it first debuted, The Toxic Avenger is set to return to the silver screen after its feature film rights have been acquired by Legendary Films. For those that may not remember, this cult-classic franchise originally hit screens in 1984 and enjoyed a run that included three sequel films, an eleven issue Marvel comic series, a cartoon series, and even a stage musical production.
The franchise was based on a 98 lbs janitor who came into contact with toxic waste, mutating him into a repulsive creature with enhanced size and strength. Billed as the “first superhero from New Jersey”, The Toxic Avenger was a brawling do-gooder based in the fictional town of Tromaville.
The team responsible for Toxie’s return will be Lloyd Kaufman and Michael Herz of Troma Entertainment, who will serve as producers. Alex Garcia and Jay Ashenfelter will oversee for Legendary.
After 44 years of filmmaking, Troma Entertainment, Inc. is the longest running independent movie studio in North America. The Toxic Avenger marks the first return to Tromaville, New Jersey by Troma Entertainment since reacquiring film rights in 2010.
The potential remake has been shopped around to various studios like New Line Cinemas and was once offered to fan-favorite writer and director, Kevin Smith. It has been rumored that Arnold Schwarzenegger was offered the role back in 2013, with no indication of whether he actually considered playing the mutated muscle-bound hero.
Are you excited to see the return of The Toxic Avenger? Comment below!
Here’s Every Hero Who Appears In The ‘Avengers: Endgame’ Trailer
Today, Marvel Studios released the first official trailer for Avengers: Endgame and revealed which heroes will likely be on hand for the re-match against Thanos.
Avengers: Infinity War united nearly every hero in the Marvel Cinematic Universe for the showdown with Thanos and after a decade of films that proved to be an extensive roster. However, the Marvel Studios epic concluded with Thanos succeeding in his mission to acquire the Infinity Stones and use their power to erase half of the universe’s population, with many of the aforementioned heroes being included among the casualties. Fortunately, the original Avengers teammates survived Thanos’ decimation and it appears they will be joined by a few the new heroes who debuted since the group initially formed when they head into the second showdown with Thanos.
Click “Next” to see a full list of heroes featured in the trailer!

domain: movie


Over-55s specialist Grand UK Holidays has introduced a new Corrie coach touring holiday, which visits the old Coronation Street set in Manchester.
The famous cobbled street will open as a visitor attraction in April and is due to run for six months until October.
It will offer fans a final chance to visit the set, where 53 years of TV history were made.
Coronation Street moved filming to Salford Quays’ Media City in November, leaving the old site redundant.
The attraction expects about 1,000 people a day will visit the soap’s former home, walk along the famed cobbles and take a peek behind the doors of some of the famous cast members’ dressing rooms in a section named ‘The Corridor of Stars’.
Harold Burke, sales director of Grand UK Holidays, said: “These tours really are a ‘once in a lifetime’ experience and if you’re a Corrie fan, this holiday will be a real treat.
“As an added bonus, our tour also includes visits to Liverpool and Blackpool, both of which also have associations with the world’s longest-running soap opera.
“We expect this new holiday to be a hit with our customers – but there is only a brief window of opportunity as developers will eventually turn the site into a new city centre neighbourhood.
“So if you want to return to the Rovers Return, time is running out!”
The five-day escorted coach holiday costs from £212pp and includes transport, admission and half-board accommodation. The departure on 22 September also includes a visit to the Blackpool Illuminations.
It is one of several new UK holidays introduced over recent weeks to cater for demand.
Different types of escorted tour have been added to the 2014 programme, including trips for solo-travellers and ever-popular Grand UK Gold holidays, which add a touch of luxury to coach tours.
For bookings, call 0208 686 2378 or see www.coachholidays.com


Free Shipping & ReturnsCanada Goose Men's Langford Parka Black Label
Canada Goose's grey tech-canvas Langford Parka Black Label is trimmed at hood with removable natural coyote fur. Zip-off fur trim at toggle-drawcord hood. Shoulder yoke at front. Angled welt pockets and hook-and-loop flap/welt pockets at sides. Logo patch at left sleeve. Rib-knit gaiter cuffs. Logo patch and webbing strap at back. 35" center back length (approximately). Concealed zip-front closure. Hook-and-loop storm placket. Lined with quilted tech fabric. Toggle-drawcord waist, vertical zip patch pocket and patch side pocket at interior. Available in Graphite (grey). 85% polyester, 15% cotton. Trim: 100% natural coyote fur. Lining: 100% polyester. Fill: 100% white duck down. Padding: 100% polyester. Dry clean. Made in Canada. Coyote fur country of origin: Canada. Our model is 6'1"/185cm and wearing a size Medium.


I wanted to make a quick post about an article I read some time ago in This Old House Magazine. It is available online and it is one of the best articles I have seen about creating a great outdoor play area that is appropriate for all ages. The design is excellent but the article also (helpfully) goes into great detail about the construction.
From the Article:
Working from a design by landscape architect Elliott Brundage, This Old House landscape contractor Roger Cook took one backyard, overgrown with bittersweet and poison ivy, and turned it into a sports lovers’ heaven, squeezing in a croquet lawn, a horseshoe pit, and a bocce court.
If you are planning anything like this, it is worth checking into.
BACK ISSUES of P+V Newspaper Are Available in the FREE Resource Library
Get A Prettier, More Organized Garden in 10 Days
JOIN THE GARDEN DESIGN CHALLENGE
Get your garden in shape so you can enjoy some peaceful & nourishing time in your own piece of the great outdoors.


Heat Resistant Reusable Silicone Rubber Coffee Cup Holder
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3. Anti-fall: It can also protect the glass from wear or breakage, and has certain characteristics of anti-fall protection;
4, beautiful: you can do a variety of shapes, you can design a variety of colors, eliminate the transparent monotonous characteristics of the glass, and increase the aesthetics;
5. Insulation: It can play the role of heat insulation after pressing it.
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text:
Calea Timisoarei 173, Drobeta Turnu Severin, Romania
This destination can have additional per person taxes which are excluded in the prices below
Located in Drobeta-Turnu Severin, Pensiunea Ioji is a short drive from Trajan's Bridge and Iron Gate I Hydroelectric Power Station. It also offers a sun deck, free Wi-Fi and a swimming pool.
Distance to city centre
Free Wi-Fi, Wi-Fi available in all areas, Internet
Pets allowed on request. Charges may apply.
Policies vary by room type and provider.
+40 745 691 488
Wine glasses, Restaurant, Bar/Lounge, Terrace/Patio, Body soap, Family rooms, Linens, Towels, Grill, Cable or satellite TV, Mosquito net, Flat-screen TV, Refrigerator, Free toiletries, Toilet paper, Outdoor dining area, Outdoor furniture, Hardwood or parquet floors, Clothes rack, Shower, Trash cans,...
Hotels in Drobeta Turnu Severin that are rated 1 star generally cost $28/night, but on average, Pensiunea Ioji is available for 15% less than the average rate in the area. You can usually enjoy a stay at Pensiunea Ioji for $24/night. This is a great deal for HotelsCombined users planning to visit Drobeta Turnu Severin.
Pensiunea Ioji is pet friendly. Feel free to bring your household pet if you’re staying at Pensiunea Ioji.
For assistance regarding your reservation at Pensiunea Ioji please call +40 745 691 488.
Yes, Pensiunea Ioji has Wi-Fi available to hotel guests.

domain: travel


text:
how cool would it be to fall for someone and that person feels the same way towards you and you both get together and fall in love with each other and be happy together like how fucking cool would that be
Ugh, I don’t want school today. There’s so much to do and so little time. I’m tired. I just want to curl up and sleep instead of studying or worrying about school so much. Yet here I am again, waking up early to study after doing a huge load of work yesterday… …
It seems like happy people don’t get it. And sad people do. People who get it and are happy, were once sad, I bet you
The true mark of maturity is when somebody hurts you and you try to understand their situation instead of trying to hurt them back.
ah yes the first pokemon battle of the game
tackle tackle tackle tackle tackle

domain: psychology


text:
Chances are that you haven’t see the moon this close before. Google Moon grant you that chance and take you back into time to view some cool maps and some photos taken on the moon from the crew of the Apollo series plus some exclusive photos from NASA.
My 2 cents
– These photos reminds me of the controversial debate of whether America really send Neil Armstrong, Michael Collins and Edwin Aldrin to land on the moon with Apollo 11.
– The Apollo series that made it to the moon were Apollo 11, 12, 14, 15, 16, and 17. Apollo 13 didn’t make it. If you haven’t watch Apollo 13 (starring Tom Hanks) maybe you should.
– Looks like Google Maps ain’t for the earth only. However, when it comes to astrology, Microsoft has probably done better then Google with their Microsoft Worldwide Telescope.

domain: aerospace


text:
I have been looking for a Hydroton replacement for a while now. As my my small system is inside on a wooden floor, gravel or river rock is too heavy. My local greenhouse supplier gave me a call last week about a product called Gold Label Hydrocorn. A single hydroponic substrate. This is supposed to be a Hydroton replacement so I thought what the heck, and bought a 45L bag. Its about the same price as Hydroton. The media is expanded clay, although not as uniform in size or shape as Hydroton. It is, for the lack of a better word, quite "lumpy" in appearance, which to my mind is a plus because of the greater surface area exposed to the fish water. I used it to top off a 40gal grow bed,and in 3" net pots in the 2*4 DWR. Herbs and spinach in it. Everything sprouted, the fish are still happy, and the water quality has not changed one iota.
I don't know if the product is available everywhere, but here is the website:
For metal analysis: http://www.aafp.org/metals.htm
Maybe this will be of use to someone in the community
I've heard good things about a product called "Plant!t". It's essentially the exact same thing as hydroton. I haven't used it myself though.
HydroCorn is indeed a suitable replacement for hydroton. It is the same pH inert, expanded clay material. It does appear to be a bit lighter than hydroton.
I use both Hydroton and Hydrocorn. One really big benefit, surface area. Hydrocorn has far more surface area than hydrocorn. Downside is it really needs to be cleaned far more than hydroton. I use Gold Medal brand from Netherlands and Hydrocorn is actually about $10 - $20 cheaper for a 45l bag.
I picked up some bags of sunleaves rocks to fill one of my 40ft grow beds. I really like them compared to hydroton. They don't roll, they don't float and the best part of all is its only $28 dollars for a 65lb bag. They are lite too, they actually feel about as lite as hydroton does. The rocks come in all different shapes and sizes. They look like they could hold some good beneficial bacteria also. A rock the size of a golf ball is really lite feeling. I will try to get some pics up soon.
Nice call Roger. Thanks for the post. At $30 per yard that is fantastic. It looks like lava with all the sharp corners melted round. BTW, save the fines for a wicking bed.
Roger Baldwin said:
This material is an expanded clay that I picked up at my local concrete batch plant. It is used for applications where regular concrete is too heavy. it weighs about half as much as the typical agregate used for concrete. It cost me $30 for a yard and has worked great in my system. It is very porous and has tons of surface area. The downside is it was very dirty and had many small particles, so I had to wash it several times over a 1/4" sieve and I lost about 1/3 of the material threw the sieve. Even after all that I had to flush my system after it had circulated through the material a few times, because of the muddy water. All of that effort was worth it because I don't have the funds to drop on designer hydroponic media.
Oh I didn't mean to say expanded clay.. oops, I was told it was an expanded shale product, but now that you mention it, it does kinda look like weathered lava. The person I got it from was not too familiar with the material, it is something they don't keep around regularly, and special order for specific jobs. They just happened to have a couple or five tons leftover. Regardless of that, they would not cut me a deal on the price... But at $30 a yard I couldn't complain. I liked it because of the weight, size, price and similar appearance to what I have seen on this sight. I conducted a fizzle test and a distilled water test on a sample before I got it and all seem good, so I bought it. Other than the amount of effort to clean it, it has been problem free. I have discarded the fines, but if... when I expand and get more I will definitely save them.
Yeah, I wasn't gonna say anything, but watch the pH of construction/concrete/drainage grade LECA. The stuff I saw here from the former producers of hydroton says pH 6.5 to 9. That's quite a range. The type and quality of clay used will determine pH and heavy metal content...That type of quality control (or lack of) is why the new owners of the company that makes hydroton supposedly had a falling out over, and hence it's not being made anymore...(The other side of the story is that a couple of the partners were wanting to edge into the more lucrative horticultural division of the business using clay from the new mine in Slovakia, or Czech Republic...I still get the two mixed up sometimes...) At any rate taking a number of 'acid fizz test samples' would be a most prudent idea...
Nope ,they don't mind enough for it to matter (as long as you have plenty of the divalent cations that tend to start to get locked out at higher pH levels present in solution). Having a bit of media that doubles as a slight buffer is indeed a keen thing. But media with a pH of 8 or 9 would be a horror. Honestly, I plan on running the new system, long term, at a pH of about 6.2. One the bacterial colony is very firmly established.
I think Rob Nash uses about 30% carbonate containing media on purpose, for the reasons you described (and I'm sure there are others). I'm sure it might make things less hands on as far as fiddling with buffering goes. But, I don't see buffering as a 'headache'
I want to run my system at a lower pH than what is generally sold as the "ideal" pH for an AP system though.


text:
Image captured by the author
Nature is poetry, infinite in age, revealing its presence in the tree rings of Redwood, Sequoias, Oaks, Pines, and cacti, while flora, fauna, and grasses surround its roots.
Nature's repetitive poetry appears along every shoreline, beach, lake, river, and pond.
Poetry is nature's desert trails, where thorny cacti stretch toward the sky.
Poetry is nature's forested trails with canopy trees, sun-light streams shimmering from above illuminating flora and fauna, filling a nose and lungs with an essence of my surroundings.
A walk, hike, or backpacking along a trail, beachfront, or shoreline is sighted poetry.
Words describe what is visually sighted, allowing your mind, body, and soul to absorb the picturesque poetic surroundings to receive its stress-relieving beauty.
Capturing nature photos for framing within a home or office, for your mind, heart, and soul to recall nature's poetic essence until your return.

domain: literature


text:
Coronation Street babe Catherine Tyldesley stole the show as she donned a plunging black dress for a gorgeous social media snap yesterday.
The former Coronation Street cast member, who played Eva Price, showed off her curves in the daring ensemble as she held a glass of prosecco.
Catherine, 36, left her fans hot under the collar in the black long-sleeved ensemble, which cinched in at the waist to show off her curves.
Her hourglass proportions stole the limelight in the figure-hugging dress, as she showed off her toned figure from her Strictly Come Dancing training earlier this year.
The outfit struggled to contain her ample assets as she laughed away from the camera as she captioned the snap: "I love a bit of sparkle at Christmas."
It didn't take long for the compliments to start pouring in, as one fan wrote: "Wow, looking cool."
Another added: "Looking fabulous."
A third chipped in: "You're infectious with a beautiful smile."
A fourth wrote: "You're so gorgeous."
This isn't the first stunning outfit Catherine has worn recently, as she donned a very festive look for her latest night out slipping into a one-sleeved scarlet gown.
Catherine looked amazing in the red-hot ensemble, which showed off her ample assets for the racy photo.
The actress, who starred in the latest series of Strictly Come Dancing, left her brunette locks bounce freely framing her flawless figure.
Taking to Instagram before heading out, Catherine treated her 600k followers to a couple of snaps captioned: "Momma's night out!!"
Corrie continues on Monday at 7.30pm on ITV.

domain: entertainment


text:
Axiom: The Scientific Computation System
by Richard D. Jenks, Robert S. Sutor
Publisher: axiom-developer.org 2003
Number of pages: 1200
Axiom is a free general purpose computer algebra system. It consists of an interpreter environment, a compiler and a library, which defines a strongly typed, mathematically correct type hierarchy. The primary philosophy is that Axiom needs to develop several fundamental features in order to be useful to the next generation of computational mathematicians. The book gives the reader a technical introduction to AXIOM, interacts with the system's tutorial, accesses algorithms newly developed by the symbolic computation community, and presents advanced programming and problem solving techniques.
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by Victor Shoup - Cambridge University Press
This introductory book emphasises algorithms and applications, such as cryptography and error correcting codes. It is accessible to a broad audience. Prerequisites are a typical undergraduate course in calculus and some experience in doing proofs.
by Justin Solomon - CRC Press
Using examples from a broad base of computational tasks, including data processing and computational photography, the book introduces numerical modeling and algorithmic design from a practical standpoint and provides insight into theoretical tools.
by Bhubaneswar Mishra - Courant Institute of Mathematical Sciences
The main purpose of the book is to acquaint advanced undergraduate and graduate students in computer science, engineering and mathematics with the algorithmic ideas in computer algebra so that they could do research in computational algebra.
by S. Basu, R. Pollack, M. Roy - Springer
The monograph gives a detailed exposition of the algorithmic real algebraic geometry. It is well written and will be useful both for beginners and for advanced readers, who work in real algebraic geometry or apply its methods in other fields.

domain: library


text:
October has come and gone. Let us take a close look at some of the very notable songs that made impact on our website and other social platforms. We aim to compose our list on what we think are the Top 10 Nigerian Songs Released in October 2016.
Missed September Edition ? CLICK HERE
10. MUSIC: Kcee ft Tekno – Tender
Five Star – Kcee starts our chart today with the release of Tender featuring TrippleMG act Tekno. I’m not sure this song lived upto expectations but its definitely a song to dance to when in the mood for party. Enjoy.
9. MUSIC: Medikal ft. Mr Eazi, Sarkodie X Criss Waddle – Free Me
Medikal is no new name in the business. He hooks up with Mr Eazi, Sarkodie and Criss Waddler to release this top-nutch tune he titles “Free Me“. Check it out below.
8. MUSIC: Phyno – Pino Pino
Pino Pino is a new track from Phyno. This is highlife tune, just so you know what to expect when you click the button. Its a brilliant song put together by the Eze-Nnunu himself. Some might argue that this song deserves a spot below, but hey – here it is.. deal with it (in the nicest way though)
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7. MUSIC: D-Black ft. Bisa Kedei – Forget Me Not
D-Black teams up with Bisa Kedei – In Forget Me Not. both act came through tight on this song. Peep it below.
6. MUSIC: R2Bees X Wizkid – More
R2Bees who recently got signed to Wizkid’s label, starts his journey under the label with a smashing single featuring Boss Wizkid. The song is titled “More” and it is definitely one song to have on that playlist.
5. MUSIC: Yemi Alde x Mi Case – Get Through This
Aunty Yemi who hasn’t really lived up to atleast my expectation recently, drops a smooth killer tune featuring Mi Case and it is called “Get Through This“. The song was produced by heavyweight Maleek Berry. Listen up !.
3. MUSIC: Iyanya ft Don Jazzy & Dr. Sid – Up To Something
While Up To Something is seen as a big song by many because of the heavyweights involved, it indeed has a short spam on playlist as one can easily get bored of the excessive repetition and no overly exciting hook. Up to Something is Iyanya’s first single since joining the Mavin’s and it features Boss Don Jazzy and Dr Did. Check it out below.
2. MUSIC: Tekno – Diana
The man of the year, who recently got nominated for Next Rated Act by Headies is one of the most in-sharp (musically) artiste at the month. He drops hit on hits. The latest rocking the airways is Diana and it is another masterpiece.
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1. MUSIC: iLLBLISS ft Reekado Banks & Mr Eazi – Jawon Laya
Oga boss dropped this tune off his just released album now on various online stores and market places. iLLBLISS seeks the help of Mr Eazi, Reekado Banks on the banger track titled “Jawon Laya“.
I don’t know what the title of the track is but it sure sound nice. Download and enjoy.