For the best cup of rich, Italian coffee, your new Moka Pot must be used correctly. You'll notice there are quite a few things to remember, but don't give up just yet. Before you know it, you'll have the process down pat and be making strong, espresso-like beverages like an experienced barista!
•	The Bottom Chamber – The bottom portion of the Moka Pot is filled with water to steam-brew your coffee. This part includes a steam-release valve for safety.
•	The Coffee Basket – This sits on top of the bottom chamber to hold the ground coffee.
•	The Collection Chamber – Located at the top of the Moka Pot, the espresso-like brew is collected in this chamber in preparation for serving.
As the water heats up in the bottom chamber, pressurized steam is forced through the coffee grounds before entering the collection chamber. Unlike standard percolators, this superior hot beverage only passes through the grounds one time for a clean flavour without a trace of bitterness.
Moka Pots naturally develop a fine film or patina that contributes to the rich flavour of the Italian espresso during use. The first time you use a new pot, it is recommended that you throw away the first few cups of coffee to allow the pot to season and the flavour to develop. If you don't use your Moka Pot for an extended period or you over-clean the coffee maker, you may need to repeat this seasoning process.
1.	Pre-Warm Your Cups – Fill your cups with hot tap water to pre-warm them. This habit keeps your freshly steamed coffee hot for longer.
2.	Disassemble Your Moka Pot and Fill the Bottom Chamber with Fresh, Luke-Warm Water – The water should reach, but not cover, the steam-release valve. Luke-warm water saves a little bit of time when you begin to gently heat the water.
3.	Insert the Coffee Basket and Fill with Ground Coffee – Ensure the basket is completely filled, but do not press or pack the coffee grounds. It's perfectly fine to overfill the basket slightly.
4.	Screw the Collecting Chamber into the Bottom Chamber – Make sure the fit is tight and completely sealed to maintain pressure and prevent leaks.
5.	Place the Moka Pot on a Flat Cooking Surface at Low to Medium-Low Heat – The intention is to steam the coffee gently. The best cup of coffee never requires a full boil.
6.	Check the Moka Pot Frequently During the Steam-Brewing Process - Over the course of about five minutes, the coffee will slowly steam through the coffee grounds and fill the collection chamber. When the water in the bottom chamber is completely used, the flow will stop. At this point, remove the Moka Pot from the stove immediately.
7.	Enjoy Your Espresso! – Pour your freshly steamed beverage into your pre-warmed cup and savor in the Italian tradition!
2.	Froth the Heated Milk – An inexpensive milk frother works well.
3.	Add Frothed Milk to the Espresso – For a perfect cappuccino, the goal is 1/3 espresso, 1/3 milk and 1/3 froth.


text:
[ARCHIVED THREAD] - Awesome range day - S&W .44 mag KB's right next to me, PICS (Page 2 of 3)
Page 1 2 3 / 3
aluminum. there is a problem with all aluminum in that it has a finite endurance limit. what this means is no matter how slight the repetitive stress, all aluminum will fail. take for example valve springs on a car, these cycle once every two engine revolutions and considering the engine must last at least 100k miles at about 2500 revolutions per mile, that means 125 million cycles. valve spring failure is very rare because they are designed for a stress well below the infinite limit which most steels have. but aluminum has no infinite stress limit.
this part of the pistol is not only highly stressed, it is also subject to notching from the cylinder gap. so most have a hard steel alloy shield. if that fails, the aluminum will become eroded and this induces a stress concentration area.
In this case, the frame is Titanium.
I don't think you're correct about that.
Shoulda bought a Ruger.
I have a 329PD; I would like to know what happened to that revolver.
I know that the blast shield at the barrel/cylinder gap can fall out; if he kept shooting with it missing I can see it eating through the topstrap and causing this.
My guess.
From S&W's Site "Smith & Wesson combined a Scandium alloy frame with a Titanium cylinder to build the strongest and lightest weight .44 Magnum revolver made."
They don't specify what the other component of the alloy is, but it would most likely be Aluminum.
After (admittedly, very little) research, mostly on wiki...it seems the most common use for Scandium is to add it to Aluminum for strength.
My 340SC, the older model, is a handful with .38 loads and is down right unpleasant to shoot with .357 loads. I would hazard to guess that the 329PD is absolutely unruly and painful to shoot.
Having said that....I'd love to have one.
A newer S&W sending its barrel downrange. Like that's never happened before.
Typical S&W quality nowadays.
If you want a good DA revolver, buy vintage or buy Ruger.
S&W used to make basically perfect guns, the quality level was amazing. Right up until about 1995 or so.
People need to understand this: the gun manufacturers have completely run out of innovations to get gun buyers excited enough to buy a new gun. So they come up with "improvements" that look good on paper but are fucking retarded.
Like ultra-light magnum guns. or lever guns that fire incredo-recoiling cartridges. or regular commercial guns recycled into dorky tacticool mode. or handguns that fire 50 bmg.
this airweight 44 mag is about the stoopidest idea i ever saw. completely absurd waste of money.
Scandium alloy frames are basically aluminum with extremely small amounts of scandium added to the alloy.
Any idea as to what caused the .44 to KB?
If I had to guess it would be that there was a hairline fracture or something caused previously by who knows what. The shots sounded normal and then one was really loud.
It was not a squib. It also was not a blockage issue.
Given that it was an airweight, I have to wonder if he was able to tell the difference between a KB and a normal discharge
44 mag out of an airweight probably feels like a KB every shot
Probably more common than it seems-non-steel frame+magnum caliber=KB waiting to happen.
While there is some truth in your post, the airweight 357s caught my interested because nothing else is as light & small, yet can pack as much punch as my 340PD. The snubbies in 38 just can't muster the same power as the 357 - or even the 9mm.
Front fell off
And, to top it all off, he even missed the bottle.
http://i122.photobucket.com/albums/o266/razor11056/05.jpg
Meh, a little superglue and that'll buff right out
Looks like he might have slammed a cheap mag home on an open bolt.
I think that part needs to be attached to the gun in order for it to work correctly.
http://www.youtube.com/watch?v=8-QNAwUdHUQ
Never miss an opportunity to post this.
I would imagine lighting that 44 off gave him one hell of a flinch!
How is this the first time that I've seen this? You guys are slacking.
The outdoor range I worked at had holes in the roof, holes in the benches, even holes through a chair (A shooter was at a bench, seated, shooting a snubby .38. The guy to his left was shooting a .45 and one of the .45 empties went down the back of this guys' shirt. The guy immediately reached back between his shoulderblades while still holding the .38. He squeezed a round off and it missed giving him an ultimate back-scratching by about an inch. Bullet went through the back of the folding metal chair he was sitting on and richocheted off the concrete deck, going up through a wooden range table and out through the sheet-metal roof.
The shooter said it was the ranges' fault, we had him too close to a guy shooting a semi-automatic, he tried to sue us, saying semi-auto's shouldn't be allowed cause hot brass could hurt someone.
I dealt with an asshole like that once on a range. The Fudd was at a bench about 2-3 spaces over, plugging away with his 1-shot every 5 minutes from his T/C pistol and I was at my bench with my Springfield 1911. I even put up a brass screen, but every few shots, a stray casing would make it over the top of the screen and land next to him. He got all offended and raised hell with the RO, and how I was breaking the rules by letting my brass land on his table. I just shrugged my shoulders, told him it was a semi-auto and WTF was I supposed to do beyond putting up a screen, and went back to shooting. Its an open air range, brass is going to go flying around and it is something you just deal with. I've been pelted with all kinds of brass over the years. The worst was some .308 brass from a FAL, but I didn't go whine to the RO about that big evil black rifle.
The front fail off.
Wasn't this one built so the front wouldn't fall off?
Apparently not
Regardless, cardboard is out.
You're missing the part about "shootability" .
Recoil and muzzle blast are serious "issues" to deal with.
You have to consider what guns you can pass the "paper plate" test with 100% of the time.
A hit with a 38 is way better than a miss with a 357.
Nowadays, another factor is ammo cost. If the ammo costs too much to practice with often the gun's usefulness is diminished greatly.
It's all about hitting the target, safety and reliability. Everything else is secondary to those three things.
Considering the real-world defensive ranges for shootings in and around this part of the country (typically 1 to 3 feet) and the large amount of practice I do at that range, I am confident with my gun choice. If my life is REALLY on the line, it will not be about measuring group size.
meh, I'd want to be able to shoot the thing at least 10 yards. paper plate test, not group size
I'm not a gunsmith, but I don't think that will buff out.
The front fell off was the first thing that came to mind when I saw the pictures
I took six guns and two brothers and one sister. Went through about 800 rounds of wolf 5.56, 300 rounds of Winchester .45, two or three hundred of .38 spl, some .22 long and .22 mags.
Pretty good day, did some drills with their computer programs.
About halfway through I noticed a barrel lying in the lane....not attached to a gun. The guy next to me was firing factory winchester. Hmmmmm
No injuries.
Good day at the range. Everything of mine ran flawlessly too until the end. My brother somehow managed to double feed it, and one of the round is now stuck above the BCG. Unsure how to proceed.....
Edit: I fixed it, thanks.
http://i122.photobucket.com/albums/o266/razor11056/083.jpg
http://i122.photobucket.com/albums/o266/razor11056/_DSC0511.jpg
UPDATED PICS FROM OWNER (there are more but photobucket is being weird)
http://i122.photobucket.com/albums/o266/razor11056/dsc_0003.jpg
http://i122.photobucket.com/albums/o266/razor11056/dsc_0015-1.jpg
Glad you fixed it. What kind of mags are you using? A double feed like that is probably the result of a magazine with shitty feed lips that isn't holding rounds inside it properly. Had it happen before with a cheap POS USA mag that I got for free with my AR15 10 years ago. My friend had it happen to him with an Orlite mag with a feedlip that broke while shooting with it.
ARFCOM THREAD
When I posted that mine was cutting through in Feb 09 I got called all kinds of lier.
You must have a short memory. Here is just one example of modern S&W quality:
N.C. wants Smith & Wesson to replace faulty revolvers
The Associated Press Faced with problems ranging from misfires to barrels breaking off, the state has asked gun maker Smith & Wesson to replace hundreds of sidearms carried by probation and corrections officers.
None of the revolvers have failed in the line of duty, and for now, the department is keeping the guns in service. But in testing, about one in four revolvers didn't fire when the trigger was pulled. In some cases, the barrel of some models broke off when the gun was fired.
"In one sense it's funny," said Chief Deputy Correction Secretary Dan Stieneke. "In another, it's alarming."
So far, the state Correction Department has asked the Massachusetts-based gun maker to replace only 500 Model 64 revolvers bought in 2004, though there have also been problems with two other models. But officials could wind up asking Smith & Wesson to provide replacements for all 5,000 of the department's revolvers.
At a meeting last month at a shooting range in Smithfield, Smith & Wesson representative got a live demonstration of the problems. During test firing of about three dozen revolvers, four misfired, meaning nothing happened when the trigger was pulled. The barrel also broke off a different model when it was fired, something that has happened 14 times in practice firings since 2003.
"On the one hand, statistically (the revolvers' performance) is not bad, but it's just the safety issue," Stieneke said. "That kind of failure gets people's attention."
Officials at Springfield, Mass.-based Smith & Wesson, one of the world's largest gun makers, did not return repeated calls seeking comment.
For at least two decades, state prison officials have used Smith & Wesson revolvers. They are assigned to probation officers and correction officers who work outside of prison walls, patrolling perimeters and escorting inmates. The guns are not carried by officers who work inside prisons, where there is too great a risk of inmates getting a gun.
The guns cost about $320 each, meaning it would cost the state more than $1.5 million to replace them all. That doesn't include the cost of buying new ammunition, holsters and other accessories, plus retraining officers to use a new model of gun.
"We're at a point where if we have to make a quick switch, it's going to cost millions of dollars, and it's going to take a lot of training and effort to get back up to speed," Stieneke said.
Many law enforcement agencies have moved away from revolvers in recent years, switching to semiautomatic pistols, something Stieneke is considering.
Information from: The News & Observer,
Copyright 2006 - The Fayetteville (NC) Observer
That's a brass whore's dream. Guessing they let you retrieve your brass (and others)?
My personal 44's are now exclusively either Ruger or Dan Wessons. They'll take the full house reloads with todays modern powders all day long without going out of time or blowing off the top strap unlike many other brands that are available.
You fell at spelling.
Just a little duct tape and it'll be fine.
I have personally owned two of the Smith 'wonder' Lite revolvers. Both of them failed beyond repair. In both instances the frames became worn to the point of being so out of spec that they could not be safely fired, and the cylinders would fall right off the crane.
Why does it appear that there are bullet strikes on the range walls, the overhead baffles, and one of the target carriers??
I'm no expert but I bet it's because there are bullet strikes on the range walls, overhead baffles, and one of the target carriers.
I haven't been to a lot of indoor ranges but every one I've been to had idiots marks like that all over it.
This range is a members only range, and I feel MUCH more comfortable at this range than ANY other indoor range I have EVER been to. I've never seen any half-wits or hooligans or blatantly unsafe behavior at this range, which is extremely unusual at a public range. I don't go to public indoor ranges any more.
I never go to indoor public ranges!
My friends do, and they tell me all these goofy horror stories of idiots just not knowing what they are doing.
The worst story was that a guy was shooting for awhile, then decided his gun worked ok, so he shot himself in the head.
The entire gun range, of course, was locked down, and the police confiscated everybody's guns, to make sure nobody else shot him.
They kept all the guns for a month or so, until they decided the suicide note that he left at home must have been real.
So instead of a shoulder thing that goes up, it had a front thing that fell off?
Fucking pussy.
I have had hot 5.56, .45, 9, and .22 ALL go down my shirt or land on my neck, etc. Yeah it burns... for a second. Certainly not worthy of that sort of reaction. Some people are fucking useless.
I'm beginning to wonder about WWB ammo.
So, do you hate field stripping your Ruger 22 pistol as much as I do mine (22/45)?
They all suck to disassemble. I have had the 22/45 MKII and a MKIII new style. I will spray the crap out of them with the bolt held open, I refuse to take those bastards apart.
Dude, it's an almost perfect pistol for hiking in bear country. My bro lives in Seattle and just got one for just that reason. It's replacing a Ruger Super Blackhawk and he says the weight difference was immediately noticeable on his last hike.
I did advise him to NOT use the Buffalo Bore 340gn hard cast rounds I got him. It's CLEARLY marked on them "For Ruger Pistols Only"
I am going to say Flame Cutting killed that revolver..
I did advise him to NOT use the Corbon 325gn hard cast rounds I got him. It's CLEARLY marked on them "For Ruger Pistols Only"
let us see him pass the paper plate test with it.
you load up the gun and put a paper plate up at a given range. however far out you can hit the plate 100% of the time is your maximum effective range
a 44 mag with a paper plate range of 5 yards is dumb.
these ultra lightweight short barrelled guns are a marketing gizmo to excite people enough to buy a new gun.
44 mag is the heaviest caliber that most people can be taught to shoot well in a reasonable period of time, i would say an airweight 44 mag falls off that chart.
look at the fracture surface on the top strap
looks to me like a clean break
as a civil engineer with some graduate study in materials, i call brittle fracture on that one
like a fatigue failure or an inclusion or imperfection at the top strap location
Pics of sister???
Didn't seem like a good idea to me either; 38Spec, OK - 44Mag...um no. Very easy to shoot fast and accurately as well.
Unpossible!!!!!!!!! Smith makes the greatest guns since Glock first invented guns.
Thus the reason you only run aluminum connecting rods for a certain amount of time and then trash them............regardless of what x-ray shows (or doesn't show)
And I dont want a Scandium frame for anything above 38/357 levels of pressure ..........sorry.
I have replica 1858 Remington revolvers with .45 Colt conversion cylinders that I would trust more than that S&W alloy frame.
Front fell off.
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Why do I want to read this book? Two words… Stacey Kade. 'Nuf said.
Despite the obvious Tom Cruisiness of the cover, (I really love the continuity but do NOT like the model they picked for Perry) I am really looking forward to the next segment in Perry and Aria's story.
I haven't heard of The Rules before this but it definitely sounds different and intrigues me. And of course Through the Ever Night is high on my list of most anticipated books in 2013! Loved the first one! Great picks!
Hehe While I was reading this first part with the "rules" it sounded like the rules in the Wicked Lovely series by Melissa Maar! The Rules sounds like a great pick!
I'm getting so excited for The Rules too!
I think The Rules sounds awesome, but the title is a little cheesy in my opinion. And the cover model for Through the Ever Night looks like he just stepped off a runway instead of out of the desert! But oh well, I loved Under The Never Sky and can't wait to check it out, too! Both sound really awesome!
Totally agree. There is no blonde shagginess. No tattoos. No Perry-ness. At least the content is promising.
The rules sounds so good but I really love the cover to through the ever night!
This is the second time I have seen The Rules today. It sounds like it is going to be really good. I am looking forward to Ever Night also. Great choices!
The Rules really caught my eye from the description.
Those both look like amazing reads. I haven't started Under the Never Sky yet but I'm super excited to!
Both books sound amazing. I haven't read the first book in the Under the never sky I really want to read it. Great picks!


text:
Altered Procollagen mRNA Expression during the Progression of Avian Scleroderma
Michael J. Ausserlechner1,
Roswitha Sgonc1,
Hermann Dietrich1 &
Georg Wick1
Spontaneous animal models of human autoimmune diseases provide the means to study the very first pathogenetic events, which is not possible in their human counterparts. This is particularly true for connective tissue diseases in which clinical symptoms become manifest only after a long and still obscure course of immunologic, inflammatory, and fibrotic processes. University of California at Davis line 200 chickens (UCD-200) develop a hereditary scleroderma-like disease resembling the entire spectrum of human systemic sclerosis, such as early endothelial cell damage, severe lymphocytic infiltration, and accumulation of collagen in skin and internal organs.
In the present study, we investigated mRNA levels of α1(I), α2(I), α1(II), α1(III), α1(VI), α2(VI), and α3(VI) procollagen and GAPDH using digoxigenin-labeled antisense probes in a nonradioactive ribonuclease protection assay (RPA). We analyzed tissue samples from comb, esophagus, heart, lung, and liver of UCD-200 chickens at different stages of the disease, and healthy UCD-058 chickens.
During the early inflammatory stage of the disease, the ratios of procollagen types VI/I and types VI/III increased 7-fold in comb tissue, followed by a 3-fold elevation in type I procollagen transcripts in the late acute stage. In the chronic stage, α1 (III) procollagen message was increased 2-fold. Additionally, hybridization with the 180 bp α2(I) antisense probe resulted in two bands of 180 bp and 115 bp, respectively, in the RPA. The ratio of these two previously undescribed bands changes in the early stage of the disease both in comb and esophagus.
In an animal model with a spontaneous scleroderma-like disease we found a characteristic, sequential increase in type VI, type I, and type III procollagen transcripts, and we found evidence for the presence and altered ratio of two mRNA variants of α2(I) procollagen, possibly caused by alternative splicing. Comparative analysis of α2(I) procollagen variants in early stages of avian scleroderma and human SSc might provide answers to unresolved questions concerning the molecular basis for generalized fibrosis in scleroderma.
Scleroderma is an enigmatic disease of unknown etiology in which fibrosis develops in the skin and internal organs in association with vascular insufficiency (1). The immune system seems to play a crucial role in the initiation and perpetuation of this condition. Investigation into the etiology of autoaggression requires animal models in which autoimmunity is induced experimentally or develops spontaneously (2–4). There are only a few animal models of hereditary spontaneous scleroderma, such as the tight skin (TSK) mouse (5–7) and the University of California at Davis (UCD) line 200 chicken (8,9). Whereas TSK mice lack important symptoms of human scleroderma, such as certain inflammatory and immunological features (5), UCD-200 chickens show numerous phenotypic and immunopathologic similarities to the human disease, i.e., early endothelial cell damage, severe lymphocytic infiltration of skin and viscera, vascular occlusion, and fibrosis of skin and internal organs (10–13). Serologically, these birds express rheumatoid factors and antinuclear antibodies (ANA) reactive with histones and DNA, as well as anticardiolipin antibodies (14,15).
One to two weeks after hatching, UCD-200 birds develop an inflammation characterized by erythema of the comb, followed by edema and necrosis within 24 to 48 hr ("self-dubbing"). The chickens exhibit severe perivascular infiltration in the skin with mainly γ/δ+/CD3+/MHC class II− T lymphocytes in the papillary dermis, and α/β+/CD3+/MHC class II+ T cells in the deeper dermis and in subcutaneous tissue. The interactions of these lymphocytes or their mediators with fibroblasts may be crucial in the initial disease stages and could cause the subsequent fibrosis with accumulation of collagen types I, III, and VI in the afflicted tissues (12).
It is believed that the excess of collagen in SSc results from overproduction by fibroblasts rather than from decreased breakdown (16). In vitro studies on cultured fibroblasts from UCD-200 chickens and human scleroderma patients revealed increased collagen production compared with normal healthy controls (17,18). However, the persistently abnormal behavior of fibroblasts from scleroderma lesions may also be due to a specific fibroblast subpopulation that exhibits an abnormal phenotype and may cause the characteristic alterations of the connective tissue (19).
We are mainly interested in the investigation of interactions between endothelial cells, infiltrating mononuclear cells, and fibroblasts leading to excessive collagen deposition. Because patients without overt symptoms are generally not yet under clinical supervision, the study of the initial stages is not possible in human scleroderma. In contrast, the rapid progress of spontaneous autoimmune disease in UCD-200 chickens allows for sequential studies beginning at the very early disease phase immediately after hatching, when no clinical manifestations are present, through chronic fibrosis stage. To elucidate the dynamics of procollagen mRNA expression in the UCD-200 model, we analyzed the mRNA levels of procollagen αx(I), α2(I), α1(II), α1(III), α1(VI), α2(VI), and α3(VI) in comb and internal organs at different disease stages using digoxigenin-labeled antisense probes in a nonradioactive ribonuclease protection assay (RPA). The rapid and well-defined progress of avian scleroderma in UCD-200 chickens allowed us to investigate changes in procollagen mRNA patterns during the progression of this scleroderma-like disease.
UCD-200 and healthy white Leghorn control line UCD-058 chickens were bred and maintained in the Central Laboratory Animal Facilities of the University of Innsbruck Medical School. The natural history and genetic characteristics of these UCD lines have been described previously (8,20).
Experimental Groups
To observe the sequence of changes in the mRNA expression patterns, tissue samples were taken from 7-day-old UCD-200 chickens without clinical symptoms (0) (n = 5), 11-day-old UCD-200 chickens in the acute phase of the disease showing the three consecutive stages of erythema (1 +) (n = 5), edema (2 +) (n = 5), and initial comb necrosis (3 +) (n = 5) (Fig. 1) and from 33-day-old (n = 5) and 8-month-old (n = 5) animals in the chronic disease stage. Healthy UCD-058 chickens, 7 days (n = 5), 11 days (n = 5), 33 days (n = 5), and 8 months (n = 5) old, served as controls. The animals were sacrificed by cardiac puncture under sodium pentobarbital anesthesia; parts of comb, esophagus, heart, lung, and liver were removed and immediately frozen in liquid nitrogen.
Spontaneous inflammation in the comb of UCD-200 chickens
Eleven-day-old UCD-200 chickens in the acute phase of the disease exhibit the three stages of inflammation (from left): erythema (1 +), edema (2 +), and commencement of comb necrosis (3 +).
RNA Preparation
Frozen tissue samples were homogenized in liquid nitrogen. Total RNA was prepared by Trisolv RNA Isolation Reagent (Biotecx, Houston, TX) according to the manufacturer's instructions. Contaminating DNA was digested with 20 units DNase (Boehringer Mannheim, Mannheim, Germany) at 37°C for 1 hr and total RNA was isolated by a second purification step with Trisolv.
Synthesis of Antisense RNA Probes
cDNA clones of chicken procollagen α1(I) pCALl (21), α2(I) pCAL3 (21), α1(II) pCARl (22), α1(III) pIN3 (23), α1(VI) (24), α2(VI) 4aU (25), α3(VI) (26), and of chicken GAPDH pGAD28 (27) were shortened and subcloned into the bacterial plasmid vector pGEM4Z for digoxigenin-11-UTP (Dig-UTP) labeling via in vitro transcription (Boehringer Mannheim) (Table 1). The quality of the antisense probes was tested in a nonradioactive RPA by using total RNA from chicken tissue, as a positive control to examine the size and specificity of the RNA probes, and yeast RNA as a negative control to exclude contaminations.
Table 1 Subcloning of procollagen cDNA fragments
Nonradioactive RPA
Five micrograms total RNA from tissue samples (in comb tissue we used 2 µg RNA) and mixtures of Dig-UTP-labeled antisense probes, 500 pg/µl respectively, were coprecipitated. Riboprobe set 1 consisted of antisense probes for procollagen types α1(I), α2(I), α1(II), α1(VI), and chicken GAPDH; riboprobe set 2 contained antisense probes for procollagen α1(III), α2(VI), α3(VI), and GAPDH (Figs. 2A and 3A). The RPA was based on the RPA n Kit (Ambion, Austin, TX). Following hybridization at 52°C, the formamide concentration in the RPA reaction mix was reduced to 11% and the mix was then incubated at 15°C for 30 min before RNase digestion of single-stranded RNA at 15°C for 30 min by RNase A/T1. Protected RNA was separated on a 6% Tris-borate-EDTA (TBE) Polyacrylamide gel and electroblotted onto a Hybond-N nylon membrane. Dig-UTP-labeled RNA was detected by chemilumines-cence; exposed X-ray films (DuPont, Vienna, Austria) were analyzed by an Elscript 440 densitometer (Hirschmann, Taufkirchen, Germany). Because the signal strength is not linearly correlated to the amount of membrane-bound RNA, we calculated an exponential fitting curve to account for the nonlinear blackening of X-ray films (M. J. Ausserlechner et al., unpublished results). Since mononuclear infiltrations during the acute phase of the disease cause an increase in the amount of housekeeping gene transcript, we calculated ratios between different types of procollagen rather than referring to GAPDH. The signal intensities of bands representing specific procollagen transcripts were added and taken as 100%.
RPA of total RNA from comb tissue of UCD-200 and UCD-058 chickens
Two micrograms of RNA was hybridized with two sets of Dig-UTP-labeled probes (set 1: antisense probes for α1(I), α2(I), α1(II) as a negative control, and α1(VI) procollagen and GAPDH; set 2: antisense probes for α1(III), α2(VI), and α3(VI) procollagen and GAPDH). Dig-UTP-labeled RNA was detected by chemiluminescence. Tissue samples were from UCD-200 without clinical symptoms (0), erythema (1 +), edema (2 +), beginning necrosis (3 +) of the comb, and from the comb of 8-month-old (8m) UCD-200 chickens in the late chronic stage of the disease, as well as tissue samples from 11-day-old (11d) and 8-month-old UCD-058 controls. (A) RPA blot: Ambion's Century-size-marker (SM) was used to estimate band size. Arrows indicate the two mRNA variants of α2(I) procollagen. In some lanes on the presented blots the lower α2(I) and the α3(VI) band are not visible since we had to find an exposure time that would show both strong bands and weak bands on the same blot. (B) Quantification: For densitometrical analysis, several films were exposed for each blot at varying times and used to calculate the relative signal abundancies and ratios of strong and weak bands via an exponential fitting curve to account for the nonlinear blackening of X-ray films. Signal intensities of the different procollagen transcripts were added and taken as 100%. The UCD-200 groups were statistically compared with age-matched UCD-058 controls by using a Mann-Whitney-Wilcoxon-U test; *p < 0.05; **p < 0.025; ***p < 0.01.
Differences between mean values were assessed for statistical significance by the Mann-Whitney-Wilcoxon U test.
Alterations of Procollagen mRNA Composition in the Acute Phase of the Disease in Comb and Internal Organs
Aalysis of total RNA from comb tissue revealed interesting correlations between the different, visually assessible stages of inflammation and the molecular levels of collagen transcripts (Fig. 1). We found no differences in the abundance of specific procollagen transcripts between UCD-200 chickens without clinical symptoms (0) and UCD-058 controls of the same age. However, in UCD-200 chickens exhibiting comb erythema (1 +), α1(VI) and α2(VI) procollagen transcripts were increased 7-fold and statistically significant elevations in edema (2 +) were observed compared with age-matched controls (p < 0.01, p < 0.025) (Fig. 2). In necrotic comb tissue, α2(VI) mRNA was elevated 6-fold compared with age-matched control animals (p < 0.025), and the proportional amount of α1(1) simultaneously rose 3-fold (p < 0.025). Sclerotic tissue from the comb of birds in the chronic disease stage (8 months), which have no inflammatory infiltrates in the remaining tissues, still expressed a 1.5-fold elevation in α1(I) procollagen and a 2-fold increase in α1(III) procollagen message compared with age-matched UCD-058 controls (p < 0.01) (Fig. 2). In internal organs, the sequential, rapidly progressing differential elevation in various types of procollagen transcripts seen in comb tissue was not detectable at the investigated time points (Fig. 3). A characteristic age-dependent decrease in type I and III mRNA was found that is similar to that described in mammalian development (28).
Analysis of total RNA from esophagus
Five micrograms of total RNA from esophagus tissue samples was analyzed using the same conditions, antisense probe combinations, and experimental groups as used for comb analysis, with the exception that 33-day-old (33d) UCD-200 and UCD-058 chickens were also examined. (A) RPA blot: Arrows indicate the two mRNA variants of α2(I) procollagen. (B) Quantification: For statistical analysis of procollagen mRNA patterns in internal organs, material from 7- to 11-day-old (7-11d) UCD-200 chickens exhibiting different stages of comb involvement was pooled and compared with UCD-058 controls. Tissue samples from 33-day-old (33d) and 8-month-old (8m) UCD-200 and UCD-058 chickens were also examined. No statistically significant differences were found between diseased chickens and healthy controls of the same age.
Hybridization Patterns of Antisense Probes in the RPA Suggest Different mRNA Variants of α 1 (I) and α 2 (I) Procollagen
Another interesting finding of possible pathogenetic significance was that hybridization of the α1(I) antisense and the α2(I) probes resulted in two bands, on the RPA blot in both diseased chickens and healthy controls (Figs. 2A and 3A). Whereas the ratio of the two α1(I) bands at 250 bp (expected size) and at 210 bp was constant, that of the α2(I) bands at 180 bp (expected size) and 115 bp (new) changed with the progression of avian scleroderma (Fig. 4). In comb tissue of UCD-200 chickens, the 115 bp/180 bp band ratio increased 4-fold at the early inflammatory phase of disease compared with controls (p < 0.025), as did the ratio 115 bp/180 bp (p < 0.025) in the esophagus of these birds. Three lung samples of both the 33-day-old and 8-month-old UCD-200 chickens were destroyed by RNase contaminations. In the two remaining lung tissue samples of 33-day-old UCD-200 birds we observed an up to 10-fold increase in this ratio and a 3-fold increase for 8-month-old birds. Unfortunately, it was impossible to detect the 115 bp band in heart and liver, since the strong GAPDH signal caused an increased background below the GAPDH band (data not shown).
Alteration of the 115 bp/180 bp ratio during disease progression in comb and esophagus
Experimental groups are as described in Figures 2 and 3; differences between mean values were assessed for statistical significance by the Mann-Whitney-Wilcoxon U test; **p < 0.025.
The investigations described here were designed to determine alterations in the procollagen mRNA patterns during the progression of avian scleroderma. The UCD-200 animal model, with its rapid and well-defined disease progress, made it possible to analyze the earliest stage of the disease before clinical symptoms become apparent, as well as the different phases of the acute stage and the involvement of internal organs. The use of nonradioactive RPA for simultaneous detection of procollagen transcripts allowed us to make clear assertions about changes in the expression patterns of the various transcripts. The high specificity of this test eliminated cross-hybridizations from antisense probes specific for the highly conserved 3′-propeptide regions of procollagen transcripts, and it allowed detection of type I procollagen mRNA variants.
Analysis of comb tissue revealed that the various visually determined stages of the acute phase were also reflected at the molecular level of procollagen transcripts. The data suggesting increased type VI procollagen mRNA during erythema and edema correspond well with reports on human scleroderma describing increased levels of type VI procollagen message in biopsies from patients in the acute phase of SSc (29). In vitro studies have shown that type VI collagen is mainly regulated by expression of the α3(VI) chain, whereas the promotor of the α2(VI) gene has some housekeeping gene characteristics (30,31). We found strong α1(VI) and α2(VI) procollagen transcript signals but relatively weak α3(VI) bands, indicating an excess of the first two transcripts, which corresponds nicely with the assumption that the amount of synthesized type VI collagen is regulated by a limiting α3(VI) procollagen chain. However, the fact that all three α-chain transcripts of type VI collagen are eievated in the same proportion could mean that an activated, strongly proliferating subpopulation of collagen-producing cells is partially responsible for fibrosis, as discussed for human SSc (19,32).
In the late acute phase, when the comb tissue is destroyed by necrosis, the proportion of type I procollagen transcripts increases 3-fold and the absolute mRNA message is still 1.5-fold elevated in old animals when mononuclear infiltrations have disappeared, which may explain the accumulation of type I collagen in avian scleroderma and human SSc (8,33). Elevation in type III procollagen mRNA in skin tissue of UCD-200 animals surviving the inflammatory stage of the disease is similar to that shown by in situ hybridization and at the protein level in skin tissue of chronic SSc patients (34,35). This characteristic elevation in type I and III collagen transcripts has been described as induced in vitro by interleukin-1 (36).
In avian scleroderma, as in the human disease, those regions exposed to higher mechanical stress (comb, neck skin, toes) are afflicted first. Pathologic accumulation of collagen has been previously described in internal organs of 6-month-old UCD-200 chickens, but not in younger animals (8). Visceral involvement obviously starts later, since the rapidly changing mRNA patterns found in inflamed comb tissue were not seen in internal organs at the investigated time points. The low survival rate of experimental animals precluded analysis of more groups in the chronic disease stage, making it impossible to detect the rapidly changing patterns seen in comb due to the large age gap between experimental groups. This is probably the reason why we detected only slightly increased levels of type I and III procollagen mRNA in 8-month-old UCD-200 chickens, since obviously, birds surviving to this age suffer from a milder, more slowly progressing fibrosis of internal organs.
The second finding, an unexpected hybridization pattern of antisense probes for α1(I) and α2(I) mRNA in the RPA, may be even more interesting. The two α2(I) bands are observed both in UCD-200 and healthy UCD-058 chickens and were not detected in a common Northern blot. However, in an RPA, even small differences in the base sequence between antisense probe and mRNA are detectable (37). Since our anti-sense probes were specific for the 3′-propeptide region of the α1(I) and α2(I) procollagen transcripts, we assumed that the reduced band size on the RPA blot was due to an alteration in the splicing site between the exons 51 and 52 of the α2(I) procollagen transcripts that caused a mismatch between probe and the alternatively spliced mRNA in the RPA, which is digested by RNase treatment. Whereas the ratio of the two α1(I) procollagen bands was relatively constant, the ratio of the two α2(I) bands clearly correlated with different disease stages in comb and internal organs. Why the ratio of these bands changes during the disease progression remains to be clarified. The elevated signal intensity of the 115 bp band could be due to increased mRNA stability or increased production of this splice variant, but these mRNA variants may also be indicators of disease onset or may play a role in the initiation of fibrosis. Further investigations will show whether similar procollagen mRNA variants are present in human scleroderma and if they play a pathogenetic role in avian or human SSc.
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This study was supported by the Austrian Science Fund (G.W., project 10830), the Legerlotz-Foundation (R.S.), and the Dr. Kolassa-Foundation for Rheumatologie Research (R.S.). cDNA clones pCAL1, pCAL3, pCAR1 were kindly provided by E. Vuorio, Turku, pIN3 by W. Bertling, Erlangen, α1(VI), α3(VI) by A. Colombatti, Aviano, 4aU by B. Trueb, Zürich, and pGAD28 by B. Auer, Innsbruck.
Institute for General and Experimental Pathology, Medical School, University of Innsbruck, A-6020, Innsbruck, Austria
Michael J. Ausserlechner, Roswitha Sgonc, Hermann Dietrich & Georg Wick
Michael J. Ausserlechner
Roswitha Sgonc
Hermann Dietrich
Georg Wick
Correspondence to Georg Wick.
Ausserlechner, M.J., Sgonc, R., Dietrich, H. et al. Altered Procollagen mRNA Expression during the Progression of Avian Scleroderma. Mol Med 3, 654–662 (1997). https://doi.org/10.1007/BF03401704
Procollagen mRNA
Procollagen Transcripts
Severe Lymphocytic Infiltration
Digoxigenin-labeled Antisense Probe
Human Scleroderma


In collaboration with the Hajim School of Engineering & Applied Sciences we are developing a biocompatible and osteoinductive material that may be used as an implant material in bone. The material under study is porous silicon. It has many advantageous features for use in skeletal repair, spine fusion surgeries, drug and gene delivery modalities and as a structural graft.


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چهارشنبه | 5 بهمن 1401
خانه/مهمترین سرکوب کننده تومور در سلول های ایمنی کشف شده است
مهمترین سرکوب کننده تومور در سلول های ایمنی کشف شده است
علی چوپانی 1 آذر 1396
مهمترین سرکوب کننده تومور در سلول های ایمنی کشف شده است - اخبار زیست فناوری
Important tumor suppressor discovered in immune cells
A team from Technical University of Munich has discovered an "emergency shut-off switch" in immune system T cells. Their results could lead to new therapies against T cell non-Hodgkin's lymphoma triggered by defective immune cells.
In the body, T cells are usually responsible for detecting and killing cancer cells. However, problems can arise when a T cell itself develops a defect in its genome. If the defect affects areas of the genome responsible for cell growth, referred to as oncogenes, the T cell itself can become an uncontrollably dividing tumor cell. In addition, the T cell, an important part of the body's defense against cancer, fails.
This is exactly what occurs in T cell non-Hodgkin's lymphoma. This aggressive form of lymphoma has a very low rate of successful treatment and afflicts approximately one out of every 100,000 persons in Germany. Prof. Jürgen Ruland, Director of the TUM Institute for Clinical Chemistry and Pathobiochemistry is working together with his team to understand the molecular mechanisms of these cancers in order to treat them more effectively.
In their new study, currently published in the journal Nature, the scientists were able to show that the defective T cells have an emergency shut-off switch, referred to as a tumor suppressor. They ascertained that the protein PD-1 can turn off defective T cells at an early stage and thus prevent them from becoming tumor cells. The researchers first discovered this function of PD-1 in a mouse model for T cell non-Hodgkin's lymphoma and were also able to explain the mechanism: PD-1 is activated by defects in genes for cell growth, known as oncogenes, and then suppresses the effect of these genes using additional proteins. Thus, it functions as a shut-off switch to prevent the uncontrolled growth of defective T cells.
The scientists also successfully resolved the question of why many T cell non-Hodgkin's lymphomas are so aggressive, in spite of this protective function. They investigated genetic data sets from 150 patients: "Based on our previous results, we intentionally focused closely on PD-1. In individual groups more than 30 percent of the patients exhibited changes in the regions of the genome that interfered with the production of PD-1. This has disastrous consequences in the tumor—PD-1 no longer functions as an 'emergency shut-off' for them. The diseased T cells can reproduce uncontrollably," says Tim Wartewig, lead author of the study.
"These patients could be helped by medications that reverse the loss of PD-1 signaling and thereby destroy the tumor cells. This type of medication already exists for other forms of cancer. In our opinion, use with T cell non-Hodgkin's lymphomashould also be considered," says Jürgen Ruland. The scientists therefore recommend investigating individual differences in tumors before making decisions about which medication is to be administered.
Explore further: Genetic link found between the immune system and lymphoma
More information: Tim Wartewig et al, PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis, Nature (۲۰۱۷).DOI: 10.1038/nature24649
Journal reference: Nature
Provided by: Technical University Munich
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مهمترین سرکوب کننده تومور در سلول های ایمنی کشف شده است – اخبار زیست فناوری
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On behalf of Robert R. Hart, Jr., Attorney at Law posted in drunk driving on Tuesday, April 11, 2017.
A video showing an overdosed Ohio man behind the wheel of a car recently made waves in the media. The man survived, but the incident is indicative of a growing opioid problem that is happening in Ohio along with several other states. According to the chief government affairs officer with Mothers Against Drunk Drivers, opioids and heroin are not normally the types of substances people abuse while behind the wheel. However, they are watching it as a growing problem.
According to the National Highway Traffic Safety Administration, 20 percent of drivers who were tested by authorities in 2014 had positive drugs tests. Another 2014 survey found that 10 million people said they had driven while under the influence of drugs. A 2011 report stated that college students were about as likely to drive under the influence of drugs as alcohol.
In a study that highlighted the dangers of driving while drugged, the NHTSA also reported that in the first nine months of 2015, traffic deaths went up more than 9 percent. Ohio was one of the states with the biggest increase in fatalities.
A charge related to driving under the influence of alcohol or drugs can be serious. Drunk driving charges may affect the careers of people who work in fields such as health care or education. An alleged DUI offender could also face legal penalties that could range from having to install an ignition interlock device on their vehicle to license suspension, fines or jail time. Therefore, a charged motorist may want to speak to an attorney about their options.


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Home › Hospital Programs and Services › C.R. Wood Cancer Center › About Charles R. Wood
About Charles R. Wood
Charles R. Wood (1914-2004) was the founder of Double H Ranch and Chairman of the Charles R. Wood Foundation. As founding father of Storytown USA (now known as Six Flags Great Escape & Splashwater Kingdom) in Queensbury, NY, Charles R. Wood was known as the "Father of Theme Parks."
In October 2001, Charles R. Wood donated $1.4 million – the largest charitable gift from an individual in the institution's history – toward a $3.85 million fundraising goal for a new linear accelerator to administer radiation oncology treatments. In recognition of this significant contribution, hospital officials renamed the hospital's community cancer center in his honor.
Charles R. Wood served as President of the International Association of Amusement Parks and Attractions. He was inducted into the IAAPA Hall of Fame in 1992. He served on the Board of Directors of the Hyde Museum in Glens Falls, NY; the International Board of the Naples Philharmonic Center of the Arts in Naples, FL; Frederic Remington Art Museum in Ogdensburg, NY; and the Board of the Saratoga Performing Arts Center (SPAC). He was also an avid collector of Frederic Remington's sculptures and many other famous works of art.
Charles R. Wood once said, "We do what we can for society but it must come from our heart."
Double H Ranch
In 1991, Charles R. Wood purchased a 300-acre dude ranch in Lake Luzerne, NY. It is a facility for children with cancer and blood diseases. Double H Ranch welcomes children from 6 to 16 years of age at no cost to them or their families. Today, the Double H Ranch has gained wide recognition for hosting more than 900 children, mainly children with cancer and other blood disorders.
To this day, the C.R. Wood Cancer Center hosts their Cindy's Comfort Camp at the Double H Ranch. Cindy's Comfort Camp is free, weekend overnight camp for children and teens age 6-17 who have experienced the death of a parent or sibling.
"I never pictured a staff so caring of my needs and concerns, but Dr. Sean Kennedy's staff, GFH's staff, and Dr. Kennedy answered all my questions, put my mind at ease, and helped me to breathe again. Thank you." Derek Slayton Queensbury, NY


Thanks to everyone who came out to our Grand Reopening Party on October 16th. Check out these great photos in the San Jose Mercury News.
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