text:
Utah Valley Muslims to break ground for new mosque
Tekakaromatagi Dammam, Saudi ArabiaJune 22, 2013 9:06 a.m.
Cool! Best wishes to them.
freedomfighter Provo, UTJune 22, 2013 9:25 a.m.
Yay! I will most definitely be visiting!
ArgoFY Salt Lake City, UtahJune 22, 2013 11:02 a.m.
Multi-culturalism is important for communities. I hope they can raise the rest of the money! It's also good to hear that most of the community is supportive. I'm sure more people will get on board with it, once they realize how nice Muslim people are overall, and as long as they don't have "allahu akbar" shouted from the minaret as a wakeup call at 4:30 every morning (like what I experienced when I lived in the Middle East).
XelaDave Salem, UTJune 22, 2013 11:07 a.m.
Having heard what some of the opposition has had to say first hand I am glad they are breaking ground because the opposition has some fairly prominent names. They of course remain in the shadows afraid to announce themselves pubiically but moving ahead at this time is prudent and wise given the opposition. Much needed addition to the culture of faith in Utah County
tenx Santa Clara, UTJune 22, 2013 12:05 p.m.
Perhaps Saudi Arabia will reciprocate and let a Mormon chapel be built in that country.
oldcougar Orem, UTJune 22, 2013 1:17 p.m.
I wonder if anyone in, say, Saudi Arabia would object if we built a Mormon Temple there? I certainly don't object to a Mosque here...but I wonder about folks being critical of opponents of this project when this is such a one-way street. Hopefully this will be an opportunity for folks with different world views and different religious beliefs to learn to live together in peace...both now, and in the long term.
davisfillmore utah, UTJune 22, 2013 2:29 p.m.
All asking is Saudi Arabia will allow an LDS branch/temple.... The Kingdom of Saudi Arabia is not the mouth-piece for Islam, Allah is. No single nation can speak for all of Islam, just like no single country can speak for the LDS religion.
jparry Provo, UTJune 22, 2013 2:57 p.m.
This is wonderful new! I'm so happy for the Islamic community and for all of us. Everything Mormons are saying in their "I'm a Mormon" campaign can be said for Muslims. Mormons and Muslims can and should be great friends with many beliefs and values in common.
Mrs TAP Bountiful, UTJune 22, 2013 4:07 p.m.
Utah would be a great place for a Muslim community. We are more open-minded here than most places in the country. The beliefs of Islam are, in many ways, very similar to those of the LDS faith, so it's easy to feel a kinship with our Muslim brothers. I hope a site will be posted where others may donate to the cause.
Esquire Springville, UTJune 23, 2013 6:46 a.m.
The United States is not Saudi Arabia, is it, folks? Maybe Utah is similar, but not the U. S.
JoeBlow Far East USA, SCJune 23, 2013 10:54 a.m.
"We are more open-minded here than most places in the country. "
Would it be safe to say that you dont travel the country much?
daveescaped HOUSTON, TXJune 23, 2013 11:05 p.m.
I have to laugh at the comments asking if a LDS chapel could be built in Saudi Arabia. Are those asking this question comparing the USA to Saudi Arabia? Do we hold ourselves to such a low standard of religous freedom?
And FYI, other Muslim countries do allow LDS chapels to be built. I worship in one each week. But I would have to agree that the standrad of religous freedome is lower in the Middle East than in most of the rest of the world. But aren't we better than that.
I have thoroughly enjoyed getting to know Muslim where I live. The Utah Valley should be glad to have them as neighbors and soon as worshipers.
Craig Clark Boulder, COJune 24, 2013 10:32 a.m.
Little known historical trivia. The LDS Church contributed money to help build a synagogue in Salt Lake City for a group of Jewish immigrants to Utah in Brigham Young's time. Also by approval from Brigham Young, the first Catholic Mass in Salt Lake City was celebrated in the original Mormon tabernacle before Catholics had their first church ready for use. Those are items Mormons can take pride in.
sg newhall, CAJune 24, 2013 10:44 a.m.
Big mistake. Religious freedom has nothing to do with islam. Islam is nothing but a political system cloaked in religious robes. The whole purpose of its existence is world domination. These mosques are dens of deceit. I for one am NOT pleased with this event. Perhaps the day when all muslims decry the violence perpetuated by their extremist factions, then and then only should we consider allowing them to build. Otherwise, muslims to not have a place in America. Sharia Law is not compatible with The Constitution. We are fools to allow muslims to entrench themselves into the fabric of American society.
Craig Clark Boulder, COJune 24, 2013 11:57 a.m.
"....Islam is nothing but a political system cloaked in religious robes. The whole purpose of its existence is world domination...."
In Joseph Smith's time, scurrilous things were said about the Latter-day Saint church which many Americans refused to see as a legitimate religion. For them, what was true about this unusual upstart sect mattered less than what they were often told by the uninformed.
Among the tragedies of 911 was in some Americans seeing the boys of 911 as somehow representative of Muslims in general. The world's entire 1.5 billion Muslim population hadn't attacked us. It was 19 young men who were social misfits in their own countries.
Image is often more defining than facts. Deeper understanding is something for which some have no patience or ambition.
atl134 Salt Lake City, UTJune 24, 2013 1:31 p.m.
You do realize that more people have died this year in the US from toddlers with guns than from terrorist attacks, right?
Kalindra Salt Lake City, UtahJune 24, 2013 4:03 p.m.
@ sg: Apparently, your beliefs are also incompatible with the Constituion.
runnerguy50 Virginia Beach, VaJune 25, 2013 2:39 p.m.
Very sad to see this happen in Utah Valley as I am saddened whenever one is buit anywhere in the United States. Why we would welcome those who have murdered so many innocent people is beyond me.
LDS Liberal Farmington, UTJune 25, 2013 2:45 p.m.
newhall, CA
"Religious freedom has nothing to do with islam."
But this is America.
And Religious Freedom has EVERYTHING to do with the U.S. Constitution.
Please stop trampling it.
John Pack Lambert of Michigan Ypsilanti, MIJune 26, 2013 11:07 a.m.
There are two LDS stakes in Indonesia. There is a temple in Nigeria which is a majority Muslim country, or at least heavily Muslim. The LDS Church has a chapel in Abuja which is largely run by Muslims. The Church also has a presence in Turkey and Malaysia, both Muslim countries in one way or another.
We are a country that believes in freedom of religion. Saudi Arabia is not. To even suggest our actions should relate to theirs is stupid.
John Pack Lambert of Michigan Ypsilanti, MIJune 26, 2013 11:13 a.m.
For what it is worth, the most intolerant comments come from people in Virginia and California.
I do have to say the comparisons to Saudi Arabia make no sense. A more reasonable comparison is to Turkey, where the LDS Church is legally allowed to proselytize.


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|1 reviews in total
*** This review may contain spoilers ***
Pippo Franco and Edwige Fenech share top billing, but 'Il Ficcanaso' (The
nosy parker) is clearly Pippo's show as he co-wrote it and dominates just
about every scene. He stars as Luiciano Persichetti, a cowardly delivery
boy who has psychic premonitions. When he starts getting mysterious phone
calls from a 'Guardian Angel' and a dead body is found in his apartment, he
becomes a murder suspect. Keeping the tone light, all of the violence
(except in a dream sequence) is done off screen, presumably so we can enjoy
Pippo's hysterical reactions.
The busy body gains a great foil when he seeks protection from an overworked, pill popping police commissioner who still lives with his mother. From the moment they meet, il commisario finds it impossible to get rid of il ficcanaso. If the writers had only been content to concentrated on these two characters, instead of crowding the film with lots of quirky characters with their own subplots, it might not have been so uneven.
Most of these (the practical joker at work, the hooker with a heart of gold) amount to very little and even Luciano's psychic abilities are rendered useless since his 'Guardian Angel' tells hem everything that is going to happen. Edwige Fenech has little more to do than to look beautiful as Suzanna, the object of Luicetti's affection who is really only interested in his ability to foresee the future.
* Spoiler Alert!*
Edwige has two nude scenes, at least one of which could easily have been done with all her clothes on. Luckily she is always a good sport about things like that.
5 out of 10
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The sketches in this volume have practically all appeared in the New Yorker. They are written with the intimacy that characterizes most of the material in that erudite publication. They have appeared at various times since 1927. The one of chief interest to physicians is the sketch of John F. Erdmann. It begins, singularly enough, with an apology because of the fear that the mere writing of it will get the doctor into trouble ethically. Mr. Busch classes Dr. Erdmann among the first ten surgeons of the United States. Other sketches in the volume include such persons of near medical interest as Henry Ford and Walter Hagen.
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See What It Would Look Like If Wes Anderson Directed Battleship
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Yesterday, Placeblooger.com launched its searchable index of local blogs, placeblogs. The local blogs in this hand-assembled directory are more than just local news sites. They are sites that provide the texture of the culture and life of their local communities. Placeblogger was developed by Lisa Williams, who runs H2OTown with advice and support from Dan Gillmore's Center for Citizen Media, Jay Rosen professor of journalism at New York University and the author PressThink and Susan Mernit at Yahoo!
At launch the list included 700 placeblogs, a number that it is expected to rapidly grow. The intent is to grow a community and resources around this form of hyper-local blogging. The site today offers a searchable index and links to a placeblogger discussion list, the first steps toward developing a.community for locally oriented bloggers.
When I first heard Lisa Williams discuss this project several months ago at a meeting of the Berkman Thursday Blog Group meeting, I was excited by how many placeblogs were included in the project. These placeblogs fill a void left by the waning of local newspapers and the growth of online media.
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text:
|Publication number
|Publication type
|Application number
|PCT number
|Publication date
|Oct 31, 2000
|Filing date
|Aug 27, 1997
|Priority date
|Aug 29, 1996
|Fee status
|Also published as
|Publication number
|Ralph Muller, Markus Sauer, Christoph Zander
|Original Assignee
|Roche Diagnostics Gmbh
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (9), Non-Patent Citations (2), Referenced by (78), Classifications (18), Legal Events (7)
|External Links: USPTO, USPTO Assignment, Espacenet
The present invention concerns a system for distinguishing at least two types of groups of molecules having different fluorescent characteristics that are bound to analyte molecules. The system performs differentiation using time-resolved fluorescence measurement and includes a light source that exposes a first sample volume to light that is suitable for exciting the at least two types of molecular groups to fluorescence. The system also includes a detector for detecting fluorescence radiation emitted from a second sample volume that at least partially overlaps the first sample volume, and a control unit that is designed to activate the light source for a time interval T1 and, after time interval T2 has passed, to activate the detector for a time interval T3. According to this system, the illumination and detection of emitted fluorescence radiation is performed at least 1,000 times per millisecond, the detector signals recorded with a recording unit during time interval T3 are evaluated with an evaluation unit, and the signal behavior over time during time interval T3 is used to determine which of the at least two groups of molecules is contained in the overlapping sample volume.
The present invention belongs to the field of chemical analysis based on detection of excited fluorescence radiation. Analytical methods of this nature have a very broad array of potential applications, although biochemistry has recently become one of the most significant applications. In particular, fluorescence radiation can be employed in order to sequence nucleic acids, as described in EP-B-0 157 280, for instance. This sequencing method produces cloned DNA strands which are broken down into fragments, the termini of which contain the fluorescently-labelled bases A, G, C, and T. Apparatuses are also known in the prior art that are described in U.S. Pat. No. 5,252,834, for instance, with which undesired background radiation can be blocked by properly coordinating the timing of the excitation light and the detected fluorescent light. The apparatus described in U.S. Pat. No. 5,252,834, however, is complex and utilizes spectral analysis of the emitted fluorescence radiation in order to identify analyte molecules.
In EP-A-0 563 998, a method for detecting biomolecules is described that is based on time-resolved laser spectroscopy. The method described here is based on the fact that the molecules to be detected are labelled with various fluorescent dyes that emit fluorescence for different lengths of time. The duration of the fluorescence signals are distinguished from each other by means of time-resolved fluorescence spectroscopy, and the emitted fluorescence is detected after the excitation light in order to suppress background radiation.
The methods and devices of the prior art described are based on the fact that there is a large number of molecules having the same fluorescence characteristics, which makes it possible to detect and characterize the fluorescent molecule. In order to accomplish this, the concentration of molecules must either be sufficiently high, or a sample volume of sufficient size must be exposed to light. Both of these methods, which are designed to capture fluorescent light from a large number of molecules, have a disadvantage in that the ensemble of molecules does not necessarily have to be homogeneous, i.e., molecules having different fluorescent characteristics may be detected. If the fluorescence radiation is evaluated based on the duration of the fluorescence, the ensemble of molecules under consideration will be assigned a common and, therefore, averaged, duration of fluorescence. This can result in the assignment being incorrect or the results being misinterpreted. Moreover, the methods of the state of the art have a disadvantage in that the presence of just a few molecules of one type can make it impossible to reliably assign them to a group of molecules due to statistical signal fluctuations and low signal intensities.
These disadvantages of the prior art are eliminated by a system for distinguishing different types of fluorescent groups of molecules according to the present invention. Using a system according to the present invention, the molecules under investigation can be reliably distinguished and assigned to certain groups even if the sample volume under investigation contains just a few or even individual molecules. Another advantage of the present invention is the fact that it is suitable for investigating very small sample volumes. This creates the possibility of greatly miniaturizing detection systems like those used in DNA sequencing.
Due to their simplicity and high sensitivity, fluorescent techniques are used in a broad spectrum of applications in the field of chemical analysis. The most prominent methods of fluorescence analysis are those that do not utilize the intrinsic fluorescence of the analyte molecules itself, but that where the analyte molecules are bound to suitably fluorescent molecule groups. Fluorescent techniques are therefore very important, especially in conjunction with immunological assays or nucleic acid detection, because they can utilize specific immunological affinities or selective hybridization characteristics of oligonucleotides to analyte-nucleic acids. The substances that are capable of binding specifically to analytes, such as antibodies or detection oligonucleotides, are hereafter referred to as detection molecules. They are bound directly or indirectly to fluorescent molecules groups. The fluorescent molecule groups selected can be chosen mostly independent from the analyte molecule to be detected in the specific case and from the substance capable of specific binding. Fluorescent dyes are preferably used that have favorable characteristics such as a high quantum yield, high photostability, and/or a suitable absorption range without this selection being considerably limited by the analyte molecule to be detected.
FIG. 1 shows the basis optical arrangement of a system according to the present invention.
FIG. 2 depicts the sample volume that is exposed to excitation light, and the corresponding sample volume on which the detection is performed.
FIG. 3 shows the course of flourescence intensity over time.
FIG. 4 shows measured results obtained form the same molecule.
FIG. 5 shows a compilation of individual measurements from FIG 4.
FIG. 6 shows a cummulative curve from a number of individual measurements performed on a single molecule.
The sensitivity of flourescent techniques is mainly limited by the background flourescence of the sample and the sample carrier. According to the present invention, the emitted fluorescent light is not detected until a predetermined length of time has passed since the fluorescence was excited. Establishing a window of time between excitation of the fluorescence and detecting the emitted fluorescence prevents the spontaneous emission of the sample or the sample container from contributing to the fluorescence signal measured. The time interval T2 between exposure of the sample volume to light and activation of the detector is preferably between 0.1 and 10 ns. Another measure for increasing sensitivity according to the present invention is to expose only a small sample volume (preferably between 0.05 and 10 femtoliters) to light that is suitable for exciting fluorescent molecule groups. This can prevent fluorescence from outside the area under investigation from contributing to the signal. Traditional methods of fluorescent analysis assume that the emitted fluorescence comes from an ensemble of molecules that comprises many thousands or hundreds of thousands of molecules. On the one hand, this ensures that the signal intensity is sufficiently high, and that the durations and frequencies of fluorescence are statistically distributed. The very small sample volumes investigated according to the invention contain only very few molecules in the illuminated sample volume. However, it was found with the invention that the duration of the fluorescence of the molecules exposed to light can be statistically evaluated even though the number of molecules is small by exposing the same sample volume to light at least 1,000 times within one millisecond, and then evaluating the fluorescence radiation emitted. This finding contradicts the views in the pertinent literature. In an article entitled "Single Molecular Detection in Capillary Electrophoresis: Molecular shot noise as a fundamental limit to chemical analysis" in Analytical Chemistry, Vol. 68, pages 690-696 (1996) by D. Chen and N. J. Dovichi, it is described that an ensemble of at least 104 analyte molecules must be present for fluorescence analysis to be performed, in order to decrease the imprecision caused by statistical fluctuations to less than 1%. Using the method according to the invention, however, fluorescent groups of molecules can be reliably distinguished even in an ensemble comprising fewer than 104 molecules. The ensemble of molecules according to the invention preferably comprises even one or a few molecules of the same type.
The present invention can be used to advantage in the field of clinical analysis, especially in the field of immunology or nucleic acid analysis. Analyte molecules can include antigens, antibodies, nucleic acids, or fragments thereof. In general, analyte molecules can be any substance to which detection molecules can be specifically bound. On the other hand, the analyte molecules according to the invention can even contain detectable fluorescent groups of molecules themselves, or be bound to them. The latter case is common in a sequence analysis of nucleic acids. The method of sequence analysis named after Sanger is one example in this context. In this method, enzymatic synthesis is used to form the counterstrand to a nucleic acid to be sequenced. According to this method, a primer is hybridized to a single-stranded nucleic acid and elongated by inserting mononucleotides. In sequence analysis performed using Sanger's method, mononucleotide analogs are used in addition to the traditional mononucleoside triphosphates, which break the chain, i.e., the strand cannot be elongated any further after such a mononucleotide analog is inserted. In sequence analysis using fluorescence analytics, mononucleotide analogs that contain a fluorescence label are used to break the chain. Different fluorescent dyes are used to distinguish between the four possible mononucleotides. According to the invention, these fluorescent dyes are distinguished by time-resolved fluorescence measurement, which makes it possible to determine which base is at the terminus of the respective nucleic acid strand. Moreover, the present invention can be used to perform nucleic acid hybridization assays. In a preferred test format, an unlabelled capture probe--usually an oligonucleotide--is first immobilized on a surface. When incubated with a sample fluid, hybridization takes place between the capture probe and the analyte (e.g., a PCR product). If a fluorescence-labelled analyte is involved, it can be detected directly, or the analyte is then detected using a fluorescence-labelled detection probe.
The present invention can also be used to considerable advantage in the detection and differentiation of fluorescent molecules in capillaries. For instance, microcapillaries with an internal diameter of from 1 to 2 μm can be used through which the fluid to be investigated flows. An optical system is used in the investigation that detects the entire cross-section--or at least a large part thereof--of part of the microcapillary so that a fluorescent molecule can be reliably detected when it passes through the capillary. Using an arrangement like this, it is possible, for instance, to sequence individual nucleic acid strands by consecutively cleaving bases from one end of the nucleic acid strand and transporting them through the capillary in their original order. The system according to the invention can also be used in conjunction with traditional techniques such as HPLC or CGE.
Moreover, the dyes that should be distinguished from each other are distinguished according to the duration of their fluorescence. The duration of the fluorescence commonly refers to the average length of time during which an excited fluorescent dye is in the excited state. The transition from this excited state into an energetically lower state takes place spontaneously, usually within nanoseconds. Since the energetic transition of the molecule is a quantum mechanical process, the duration of the fluorescence of an individual molecule is undetermined, and the range of durations of the fluorescence observed under experimental conditions is given by the Heisenberg uncertainty principle. In order to determine the duration of the fluorescence of a type of molecule according to the prior art, an ensemble of molecules of sufficient size is exposed to light of a suitable wavelength, and a large number of molecules are excited. The transition of molecules to the final state usually takes place according to kinetics of the first order, so that an exponential decay law applies. By integrating the differential equation involved, one obtains the signal intensity as it relates to time. The duration of the fluorescence can be deduced by evaluating the course of the signal over time that is determined. If kinetics of the first order apply, this is the time after which the fluorescence intensity has decreased to 1/e. According to the invention it was found that the duration of the fluorescence can also be determined for individual molecules if a proper approach is chosen. The mean duration of the fluorescence is determined by exposing the same sample volume to light that is suitable for exciting the fluorescent group(s) of molecules at least 1,000 times within one millisecond. In evaluating the fluorescence signals determined, it is assumed that the same type of molecules are contained in the illuminated sample volume during each of the measurements. This is achieved according to the invention by investigating a small sample volume (preferably between 0.05 and 10 femtoliters) and using a suitable procedure to ensure that basically only molecules having the same duration of fluorescence are contained in the illuminated sample volume. It is also important according to the invention that the measurements in the sample volume be performed within a short period of time--preferably within fewer than 50 milliseconds--to prevent diffusion processes from having an interfering effect.
Fluorescent dyes that are suitable according to the present invention also have a sufficiently high photostability, i.e., the dyes can undergo a large number of excitation and decay cycles without decomposition. The dyes named in EP-A-0 563 998 have proven to be especially suited. Dyes from the class of rhodamine derivatives, oxazine, and carbocyanines are particularly suitable. According to the present invention it is advantageous to use at least two types of fluorescent molecules having different durations of fluorescence. This usually means that the fluorescent molecule groups as such are different. According to the invention, however, differentiations can be performed in which the fluorescent groups of molecules are identical, but in which a detectable change in the duration of the fluorescence takes place as a result of the interaction of the fluorescent molecule group and the molecule bound to it.
A system for distinguishing fluorescent dyes using time-resolved fluorescence measurement includes a light source with which a first sample volume is illuminated. Suitable light sources in particular are lasers, preferably diode lasers and flash lamps. The light sources must be sufficiently intensive and be repeatable at high frequency. The latter characteristic is given when the light source can be activated and turned off at short intervals. The repetition frequency of the light sources used is preferably greater than 10 MHz and has pulse half-widths of less than 1 nanosecond. The emission range of the light sources used is selected so that the light is sufficiently strong in the absorption range of the fluorescent dye--preferably greater than 100 mW. On the other hand, the fluorescent dyes can be selected based on a suitable absorption range if a suitable light source is already present.
Due to the main application of the system according to the invention for aqueous solutions, light sources with emission wavelengths above 600 nm are preferred. An application of the present invention in the near infrared range has proven to be particularly advantageous, because the fluorescent background radiation through the sample is low in this case, and suitable dyes are available that emit fluorescence for different lengths of time. In the especially preferred wavelength range of 630 to 670 nm, there are only very few molecules that can be excited to fluorescence, so the natural background fluorescence in this range is particularly low.
The first sample volume can be exposed to light directly from the light source, i.e., without optics situated between the two, if the light beam emitted from the light source is focused properly to ensure it hits the very small sample volume used according to the invention. However, the excitation light beam is preferably focused through a microscope optics onto an area of the sample. It is advantageous to capture the fluorescence radiation emitted by the sample with the same microscope optics and to send it to a detector. By using the same optics to output the excitation light and capture the fluorescence radiation, it can be ensured that the signals detected come from a narrowly restricted area. By using microscope optics, an aperture limits the area in the direction of the beam by the decreasing focus as the distance from the focal plane increases. In the plane vertical to the beam axis the sample area is restricted by quality of focussing and the aperture.
According to the invention, the sample is illuminated and the fluorescence radiation is detected in such a way that a first sample volume is exposed to light and the fluorescence radiation from a second sample volume that at least partially overlaps with the first sample volume is detected. An especially good overlap of illuminated and evaluated sample area can be achieved if the same optics are used to output the excitation light and capture the fluorescence radiation.
As an alternative to the embodiment described above, the sample can be exposed to light from the light source in a first direction, and, independently, the fluorescence radiation emitted can be captured in a second direction using microscope optics. These steps are preferably carried out in a 90� arrangement, i.e., the excitation and detection beams are at right angles to each other.
Fluorescence radiation emitted from the sample is directed through an optical system--preferably microscope optics--to a detector. Optical filters that filter out background radiation can also be situated in the path of the detection beam if necessary. However, one advantage of the present invention is that it does not require optical filters. When using microscope optics to capture emitted fluorescence, the beam bundle exiting the microscope optics is focused onto a detector by means of another optical system. By using this confocal arrangement, detectors with a small active surface can be used. The diameter of the detector surface is preferably less than 500 μm. Suitable detectors also have a high sensitivity to facilitate evaluation of the low intensities that occur with the arrangement selected. Semiconductor silicon detectors are especially suited due to their high quantum efficiency of up to 80% in the NIR range. If, on the other hand, photomultipliers are used that have a relatively large, active detector surface, a spacial filter (pinhole) in the beam path is used to limit the surface.
The detector is activated after the light source is activated and a waiting period T2 has passed. The detector is activated for about 1 ns, and the time resolution of the signals is about 300 ps. The detector can be deactivated for a longer period of time, but should not to exceed 10 ns.
The detector signals are captured by a recording unit. A recording unit comprises a very fast converter for converting analog detector signals into digital values, which are stored. The digital values are preferably evaluated in real time, although can be evaluated delayed. A common microprocessor can be used to evaluate the digital values.
The detector signals obtained in the time interval T3 --after digitization and further electronic processing, if necessary--are stored in memory locations assigned to individual time intervals. A memory of this nature comprises 100 or more memory locations, for instance, that are assigned to consecutive time intervals. A time interval is preferably within the range of 0.01 to 1 nanoseconds. If a fluorescence process is detected 5 nanoseconds after the sample is exposed to light, for instance, a value will be stored in the memory location that covers a decay time of 5 nanoseconds. The value can be proportional to the signal intensity detected, although a unit value is preferably stored that shows that a fluorescence process has occurred with a duration in the duration interval indicated by the memory location. In an especially preferred application, the signal obtained by the detector can also be analyzed with regard for signal intensity, and the number of individual molecules from which the signal was emitted can be determined. The multiple of the unit value corresponding to the number of molecules in this embodiment is stored in the memory location.
The storage process described above is carried out for each measurement, and a summation is performed. This means that the unit value--or a multiple thereof, if necessary--to be stored in a certain memory location after a measurement is performed will be added to the value already present in the location. The cumulative curve that is obtained this way with the measurements for a certain sample volume can be evaluated in order to determine which fluorescent group(s) of molecules is (are) contained in the sample volume. The same evaluation methods can be used with the cumulative curve that are used for signal curves obtained with a large ensemble of molecules. By recording the absolute number of fluorescence events to precisely a few tens of picoseconds, a global analysis of photon statistics can be performed. Characteristic accumulations or pauses in the global photon distribution can be detected and determined. This makes it possible to measure the triplet life of a system and to determine the reaction kinetics. In addition, diffusion times can be measured this way via the detection volume, which can be used to deduce the size of the analyte molecule. Preferred methods for evaluating the cumulative curves obtained using the method according to the invention are described below.
Using a system according to the invention, a total collective photon efficiency of 5 to 10% can be achieved, based on the number of photons used for illumination. This results from an absorption efficiency of fluorescent dyes of approximately 80%, a probability of emission of approximately 90%, and a detector sensitivity of up to 70%. It was found that about 200 detected fluorescence events are sufficient to keep the uncertainty of the differentiation below 10-4. At concentrations of 10-9 to 10-12 mol/l, 5,000 measurements on the same sample volume are sufficient, and 10,000 are better. This indicates that a sample volume with a measurement cycle in the MHz range can be investigated according to the invention within a few milliseconds or less. It was found that the following relationship exists between concentration c[mol/l], measuring time T[s], and detection volume V[l] for a fluorescence event to occur:
c=l/(v�T)�10-26 mol�s
Measuring time T refers to T3 �A, with A indicating the number of cycles in which activation and detection take place.
If the expected concentration is known, the detection volume and/or measuring time can be selected so that a number of fluorescence events is obtained that is sufficient for evaluation.
A system according to the invention also comprises a control unit that is designed to activate the light source for a time interval T1 and, after a time interval T2 has passed, to activate the detector for a time interval T3. A control unit of this nature is suitable for facilitating time-resolved fluorescence measurement. The time interval T1 at which the light source is activated is used to transfer analyte molecules in an excited state from which they change into an energetically lower state by emitting fluorescent light. The time T1 is preferably in the range of 100 ps. The waiting period T2 is used to exclude from the measurement any spontaneous fluorescence from the sample that is not emitted from the molecular group to be detected. The time T2 preferably lies in the range between 0.1 and 10 ns. The detector is activated during time interval T3 and detects fluorescence radiation emitted from the sample. The time T3 is preferably selected between 20 and 100 ns. During this T3 period, the signal intensity and time of occurrence of the detector signals are recorded by a recording unit. Since the measurement is performed on individual or at least a few molecules, a classic fall-off curve for fluorescence is not obtained in the time interval T3. Rather, a signal peak is obtained for an individual molecule that identifies the time of occurrence and/or the time interval in which the individual molecule emits radiation. Since the measurement is repeated, a statistical evaluation can be performed from which the duration of the fluorescence lifetime can be determined. The determination of the duration of the fluorescence on one or a few molecules is problematic at first, because many molecules decompose after repeated excitation and are therefore not able to survive the number of measurement cycles required to perform an evaluation. In accordance with the present invention, fluorescent molecule groups are preferred used that survive at least 1,000 fluorescence cycles. Due to the small sample volumes used with the present invention--preferably in the range of 0.05 to 10 femtoliters--steps must be taken to ensure that the molecule or ensemble of molecules investigated do not move out of the sample volume under investigation during measurement as a result of flow or diffusion processes. The invention takes this situation into account by performing at least 1,000 measuring cycles per millisecond. Moreover, suitable statistical methods must be used to evaluate the measured results.
The maximum likelihood method and pattern recognition have proven to be especially suitable for statistical evaluation with the present invention. The signals obtained during the detection cycles T3 are added up in the memory timely resolved for statistical evaluation. This means that the intensity measured in various measuring cycles at a certain time interval within T3 are added up. This is performed for a sufficiently large number of different time intervals (e.g.: 1,000). The sums of intensities contained in the individual memory locations are proportional to the probability that the ensemble of molecules investigated emits fluorescence radiation within that time interval.
Using the maximum likelihood method, a duration of the fluorescence is now estimated and the probability is calculated with which the probability distribution measured under experimental conditions would have been obtained with this duration of fluorescence. The duration of the fluorescence that results in the highest probability is called the maximum likelihood estimator and is the result of the statistical evaluation. The maximum likelihood estimator is compared with the durations of the fluorescence of the different types of fluorescent molecule groups that were used in the investigation. The type of fluorescent molecular group that lies as close as possible to the maximum likelihood estimator was present in the sample volume investigated.
In the second statistical method--pattern recognition--the intensities obtained in a certain time interval within T3 are added up as described earlier. Sample detection is performed with the following mathematical formula: ##EQU1##
In this formula, N is the sum of all photons counted over the time period T3. The number of photons counted in time interval i are indicated with ni. pi (j) indicates the probability that a fluorescence event will occur in the time interval i if the substance measured is of type j. The numbers of photons ni therefore represent the timely signal of the measurement performed, while pi (j) indicates the pattern of the signal for a certain substance. Using this formula, the molecule or molecules in the sample volume measured is (are) assigned to the type of fluorescent molecule group for which the value I* is smallest, taking the corresponding pi (j) as the basis.
The present invention is described in greater detail using the following figures:
FIG. 1: Optical arrangement
FIG. 2: Sample area that is evaluated
FIG. 3: Course of a measuring procedure over time
FIG. 4: Results of individual measurements
FIG. 5: Cumulative curve of individual measurements
FIG. 6: Cumulative curve from a number of individual measurements performed on a single molecule
FIG. 1 shows the basic optical arrangement of a system according to the present invention. In the example shown, the sample fluid is contained in a capillary (10), part of the internal space of which is projected on a detector (2) by means of microscope optics (1). An aperture (3) is situated in front of the detector to blocks background radiation. A beam splitter (4) is situated between the microscope optics (1) and the detector (2), by means of which the light from an excitation light source (5) is coupled into the microscope optics (1). The excitation light source in the example shown is a model PLP 01 diode laser from Hamamatsu. Using this diode laser, repetition rates of 10 MHz with pulse widths of <100 psec and pulse peaks of greater than 50 mWatt can be achieved.
The fact that the excitation radiation is transmitted by the same optics with which the fluorescence radiation is captured means that a very small area of sample volume is selectively exposed to light, and the fluorescence radiation emitted from this area is evaluated. This procedure makes it possible to very precisely define the space of the sample volume investigated and prevent the measurement from being interferred with by fluorescence from outside the area investigated.
The detector (2) shown in FIG. 1 is a time-correlated single photon counter in the form of an avalance photodiode. Avalance photodiodes can be used to advantage in the field of time-resolved fluorescence spectroscopy, because they have a small detection area as compared with photomultipliers. Avalance photodiodes can therefore be used in confocal optics in particular, in which the space of the sample volume to be investigated is situated in the focal point of a first lens system, while the detection surface of the photodiode is situated in the focal point of a second lens system. With this design, only light from the desired area reaches the photodiode. This arrangement can greatly reduce the background fluorescence.
FIG. 1 also shows that the ends of the capillary (10) are in liquid contact with two reservoirs containing sample fluid. Both of the sample fluids are connected with a pole of a voltage source (not shown), so that analyte molecules can be transported electrophoretically through the capillary.
FIG. 2 depicts the sample volume (first sample volume) that is exposed to light from the excitation light source, and the corresponding sample volume (second sample volume) on which the detection is performed. In the ideal case, the areas shown overlap completely. In an actual case, however, the areas are shifted towards each other somewhat, so that the overlapping sample volume in which the measurement is performed is an intersection of the two volumes. The relationships shown occur when a focused excitation light beam is used and confocal detection is performed. The volume areas shown in FIG. 2 are laterally delineated by the construction of the formation lenses and aperatures, and the diode surface which acts as an aperture. The volume areas are delineated transversally by the focus range of the optics in conjunction with an aperture that excludes unfocused beams.
FIG. 3 shows the course of fluorescence intensity over time as it can be obtained by creating a cumulative curve from many individual measurements using the method according to the invention. An excitation light impulse with a high edge steepness occurs in time interval T1. With the system according to the invention, the fact that the leading edge of the excitation pulse is steep is not the only factor, but also that the light source is turned off very quickly. Particularly the time interval T1 should be very small as compared with the duration of the fluorescence. The excitation light pulse is followed by time interval T2 in which neither the light source nor the detector are activated, in order to exclude any spontaneous background fluorescence that occurs during this interval. The cumulative curve in time interval T3 is a statistical representation of the fall-off of fluorescence emission over time. The duration of the fluorescence of the fluorescent groups of molecules can be determined from the cumulative curve.
FIG. 4 shows measured results obtained from the same molecule. The time that has passed since the molecule was exposed to the light source is plotted on the x-axis on each of the graphs. A unit value for a detection signal that is obtained is plotted on the y-axis. The gray-shaded box in each of the graphs indicates the time interval after which the molecule was exposed to light in which the fluorescence radiation imitated by the molecule was measured. Since the fluorescence emission is a statistical process, the fluorescence emission in the individual experiments is also detected for the same molecule after different lengths of time.
FIG. 5 shows a compilation of individual measurements from FIG. 4. The unit values obtained with the individual measurements are added up for the individual periods of time. This produces a diagram that shows how often a certain range of the duration of the fluorescence was obtained with the measurements.
FIG. 6 shows a graph corresponding to FIG. 5, but with a much higher number of individual measurements. The points shown in the figure indicate the number of times with which a certain interval of duration of the fluorescence was obtained with the measurements. The length of time between the moment the molecule was exposed to light until fluorescence radiation is emitted is plotted on the x-axis. The line drawn in the figure is a statistical representation of the fall-off of fluorescence intensity. In the actual experiment, the statistically determined duration of the fluorescence is 3.7 ns.
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|Taylor Lansing D
|Protein-Protein Interaction Biosensors and Methods of Use Thereof
|Sep 18, 2009
|May 6, 2010
|Singulex, Inc.
|Single molecule assays
|Apr 3, 2008
|Nov 25, 2010
|Goix Philippe J
|Highly sensitive system and methods for analysis of troponin
|Mar 25, 2010
|Dec 30, 2010
|Singulex, Inc.
|Methods and Compositions for Highly Sensitive Detection of Molecules
|Jun 7, 2010
|Jan 6, 2011
|Singulex, Inc.
|Highly Sensitive Biomarker Panels
|Oct 12, 2010
|May 12, 2011
|Singulex, Inc.
|Highly Sensitive System and Method for Analysis of Troponin
|Nov 9, 1999
|Oct 24, 2001
|Raytheon Company
|Method and apparatus for performing cell analysis based on simultaneous multiple marker emissions from neoplasia (casmmen)
|Sep 11, 2013
|Mar 20, 2014
|Force Diagnostics, Inc
|Rapid tests for insurance underwriting
|U.S. Classification
|435/6.11, 435/7.1, 359/368, 536/24.3, 536/24.32, 204/452, 250/282, 435/283.1, 250/458.1, 536/24.31
|International Classification
|Cooperative Classification
|European Classification
|May 22, 1998
Owner name: BOEHRINGER MANNHEIM GMBH, GERMANY
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MULLER, RALPH;SAUER, MARKIUS;ZANDER, CHRISTOPH;REEL/FRAME:009268/0081;SIGNING DATES FROM 19980421 TO 19980513
|May 27, 1999
Owner name: ROCHE DIAGNOSTICS GMBH, GERMANY
Free format text: CHANGE OF NAME;ASSIGNOR:BOEHRINGER MANNHEIM GMBH;REEL/FRAME:009971/0915
Effective date: 19990104
Owner name: ROCHE DIAGNOSTICS GMBH,GERMANY
Free format text: CHANGE OF NAME;ASSIGNOR:BOEHRINGER MANNHEIM GMBH;REEL/FRAME:009971/0915
Effective date: 19990104
|Mar 23, 2004
|Fee payment
Year of fee payment: 4
|Mar 20, 2008
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|Jun 11, 2012
|Maintenance fee reminder mailed
|Oct 31, 2012
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|Dec 18, 2012
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Effective date: 20121031


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101 Ways to Die is a darkly humorous physics puzzle game from indie developer Four Door Lemon that will task players with finding creative ways to violently kill hordes of innocent, zombie-like creatures. It's silly puzzle game dripping with cartoonish violence.
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iPodlounge growth drives expansion, rebranding to iLounge
A Message from Dennis Lloyd, Publisher of iPodlounge
Back in 2001, I started iPodlounge as a place for iPod owners and admirers to learn about the world's coolest invention. The idea was simple: create a friendly, relaxed lounge where good people could hang out and meet other good people.
In our first few months, hundreds of visitors checked out the site, telling their friends and families about both the iPod and iPodlounge. They kept coming back, so it's no surprise that iPodlounge has grown. Now we have a community of over 65,000 forum members, over 3,000,000 visitors a month to our main site, comprehensive coverage of every iPod ever released (plus every major iPod accessory), and some of the most incredible photo galleries ever assembled. This past month, we had over 20,000,000 page views, and thanks to your readership, the numbers just keep going up.
Today I have some exciting news to share: iPodlounge is expanding. For years, we've been known around the world by our name and our famous tagline, "All Things iPod.
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Message Subject
Human survivability with supply chain disruptions and its effect on populations
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Some people are in transit at any time on the highway. What happens to them?
When an economic collapse happens, a lot of people, who ordinarily use the highways, could end up stuck in traffic jams. It mostly depends upon when any exodus occurs to look for fuel or stock up on supplies. If it happens around rush hour peak periods when people are going to work or coming home, then a lot of people could easily be stuck in the madness of the moment.
Many retirees have a lot of free time and travel based upon whim. They could find themselves stuck behind miles of traffic.
People leave for school or return again when attending a commuter college. School children could be stuck on buses. Day care or elder care often take people on an activity.
Salespeople could be traveling to or from their client and on to the next call.
Real estate agents could be coming or going from a house viewing or an open house.
People attend seminars, and save money on air fare by driving instead.
All of these people are at risk in a dollar collapse due to the supply chain issues. Most will not have any supplies in their car, will be improperly dressed for walking, probably won't have more than $50 on them, won't have maps to know about alternative routes.
In Winter, it is wisdom to have some extra things in the trunk, gas up your vehicle, keep it well maintained, have some supplies, extra money, dress for the weather, have some walking shoes, etc. It's just common sense.
Anyone on the highway in a dollar collapse could be stranded and unable to safely get home. A lot of people are thinking it's no big deal to walk 20 miles. It's true that people can easily walk 20 miles on flat terrain like a road, but think...is the road the best path if things are out of control? Or is it smarter to take alternative side roads, walking a little off the highway, shadow the road by walking through a forest with cover in case there are issues, etc? Walking 20 miles this way is quite a bit more of a physical activity and at the average pace of a seasoned hiker on the Appalachian Trail, and not in the average ability of most Americans. Imagine hiking that way with your grandma or a four year old. You probably will have issues.
What happens if physically challenged? What if you're pregnant and quite far along?
What happens if there's trouble ahead as you're attempting to get home? What happens if challenged? What happens if you witness someone being assaulted? Troubling, isn't it?
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A leader may impose price controls, just as governors impose them in disasters.
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The River
By Garth Brooks
Choir Sacred
Composed by Garth Brooks and Victoria Shaw. Arranged by Carl Strommen. This edition: Accompaniment Cassette. Choral Octavo. Pop Choral Series. Sacred. Cassette. 1 pages. Published by Alfred Music (AP.2805RCTX).
Item Number: AP.2805RCTX
Garth Brooks' hit is set in a folk style which showcases the moving text of this song. 'You know a dream is like a river, ever changing as it flows...' A strong message in a strong arrangement!
About Alfred Pop Choral Series
The Alfred Pop Series features outstanding arrangements of songs from the popular music genre. These publications provide exciting, contemporary, and educationally-sound arrangements for singers of all ages, from elementary through high school, to college and adult choirs.


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(based on 394 reviews)
Ratings Distribution
5 Stars
4 Stars
3 Stars
2 Stars
1 Stars
of respondents would recommend this to a friend.
Best Uses
Reviewed by 394 customers
Displaying reviews 11-20
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« Previous | Next »
(2 of 2 customers found this review helpful)
Didn't work for me
By Katharina
from Zurich, Switzerland
About Me Beauty Conscious
Comments about SKIN BALANCING Pore-Reducing Toner - 6.4 oz:
I purchased three products: the Skin Balancing Pore Reducing Toner, the Calm Redness Relief 1% BHA Lotion Exfoliant and the Shine Stopper Instant Matte Finish. While the Exfoliant and the Shine Stopper do everything they claim the Toner doesn't work for me. It irritates my skin. I applied it in the evening before my moisturizer and my skin immediately became red and blotchy. In the morning I applied it before my sunscreen and again, my skin became blotchy. If I just apply my moisturizer and then the exfoliant my skin looks great. I tried using this toner for several days thinking that my skin will get used to it. But the toner has still the same effect - it irritates my skin.
Bottom Line No, I would not recommend this to a friend
Customer Service Response: Hello, and thank you for sharing you experience with us - we're sorry to hear this didn't work as expected for you! Please contact a member of our Customer Care team, who can assist you with a possible exchange or refund.
Was this review helpful? Yes / No
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(4 of 4 customers found this review helpful)
Better Then ones I have used before.
By Feather
from Fresno, CA
About Me Brand Buyer
I have used others, primarily between Pro Activ & Clinque when comparing toners. I can honestly say this does not dry my skin out and leave a tight feeling. I feels like a nice step after the cleanser. Plus it does not burn even swiping over acne like some I have had tried.
Bottom Line Yes, I would recommend this to a friend
(5 of 6 customers found this review helpful)
great "starter" toner!
By Madeleine
from Boston, MA
About Me Budget Buyer
Before I started using PC products I was used to so-called toners that left my face feeling dry and tight, and though I didn't know it at the time, left my skin irritated and did more harm than good. I associated the feeling with being clean. This ended up not being the perfect toner for my face, but only because I have different needs (so it still gets 5-stars!). BUT I would have HATED going directly to a toner with a milkier texture. This toner is nice and light and actually helped my skin. It provides light moisture. If you are new to toners and don't know where to start, I would recommend trying this first as a transition.
By Karen
from Toronto, ON
I refuse to use another toner after finishing an entire bottle of the Paula's Choice Skin Balancing Toner. This toner is great because it removes every trace of oil or make up residue without drying the skin. It's a great product to ensure that the pores are clean and helps other skin care products work a lot more effectively! I use it before using the Paula's Choice 2% BHA liquid and the combination has improved my skin complexion immensely!
I used 12 bottles in last year of 2015!
By QiangYu
from CA
I'm a big fan of Paula's Choice. I used 12 bottles of this toner in last year,which means every month i have finished one. I love this toner, and the price is very reasonable.
(4 of 7 customers found this review helpful)
Unfortunately it made me break out
By JPWillaims
from St. Louis, MO
I was so excited to purchase this product since a friend of mine uses it daily. I even tried a sample for a couple days and didn't seem to have any side effects after use. After I purchased the product and and used it for a few weeks, I started breaking out. I immediately stopped using and the product and the acne went away. If you are prone to cystic acne, you may want to reconsider purchasing.
Customer Service Response: Hello, and thank you for sharing your experience with us - we're sorry to hear this didn't work as expected for you! Please contact a member of our Customer Care team, who can assist you with a possible exchange or refund.
(1 of 1 customers found this review helpful)
This is my "holy grail" toner!
By ChantaLoveSkincare
from Roy, Wa.
I user PC Skin Balancing Pore-Reducing Toner 2 times daily (am/pm) after cleansing and before applying other treatment(s)/moisturizer. I discovered Paula's Choice about 2 years ago - and am hooked! I've noticed a huge difference in my skin and feel this toner plays a big part. It's nonirritating, the product applies easily and evenly over my skin when applied with a cotton ball, and I feel is a great way to start my skin care routine each day - weather it be in the morning prepping my skin for makeup or in the evening after cleansing and taking my makeup off for the day - I know the products that follow will be more "effective" starting with this toner. < 3 Paula's Choice!!
(7 of 10 customers found this review helpful)
Viva La revolutions
By Bonnie-Tastic
from Woodstock, Ontario, Canada
VIVA LA REVOLUTION!So I started a Skin Revolution on my face March 8th 2016.Today is Mach 17th 2016, and I can already see a difference. Let me break it down for you.Skin concerns:1. GIAGANTOR Pot Hole Pores. (That's top of my list)2. Skin Texture (I have some weird texture up by my eyes/tops of cheeks)3. Oily Combination Skin4. Fine Lines and wrinkle prevention. Plan of Daily Attack!1. Body Shop Tea Tree Skin Clearing Facial Wash2. Paula's Choice Skin Balancing Pore-Reducing Toner3. Paula's Choice Skin Perfect 2% BHA liquid Exfoliate4. DAY: Paula's Choice Clear Ultra-Light Daily Mattifying Fluid SPF Moisturizer5. NIGHT: Body Shop Nurtiganics Night Cream6. Clay Mask 1-2/week: Sephora Brand Mud Mask Purifying & MattifyingNow I am by no means admitting that you can actually shrink your pores… this is a giant misconception. We need them, they do good things. However; mine are so large that they get clogged up easily thus making them appear larger. Paula's Choice Skin Balancing Pore-Reducing TonerI always thought tonners were a gimmick up-sell. That they really didn't do much for your skin, or that people prone to acne needed them and not me. I found that in the past when I used them, it would dry out my skin and break me out. Even if I used sensitive skin ones, as I thought for the longest time I had sensitive skin. Not true. A GOOD tonner should not be alcohol based. That will make anyone's skin sensitive; thus breaking you out cause you are drying up any moisture in your face causing your skin to produce more oil thus creating a never ending cycle of breakouts and dry/oily skin. I thought I would give this one a go. I feel that it is probably why I didn't break out during reformatting my skin regime. Good tonners repair damage to the skin and help restore skins natural PH so it doesn't go in hyperactive mode to produce what its lacking (AKA Oil). No matter how gentle a face wash is; when you wash away your skins natural moisture it needs to repair itself. Tonners help do the work for you, and you get to have clear nice skin as a side effect… sounds like a win win in my books!
(8 of 8 customers found this review helpful)
Icing on the cake
By Elle
from Mississauga
Horrid acne with an oil slick before I started. Used the Clear Regular Strength kit plus this and Resist moisturizer. The clear kit takes care of the acne, but this over time truly balances oil production. The effect didnt become notable until the bottle was almost done. It does not over dry, or over moisurize. It also preps the skin for the exfoliator or whatever else you choose. I ran out and realized this product's exact contribution to my skincare routine. Without it my skin is a little tight, and after a 2-3 days starts becoming oily again. The other products do the heavy lifting and this is the icing on the cake.In regards to pore minimizing, the pores on my nose shrink, otherwise it doesn't fix ice pick scars and potmarks but I'm currently using the scar serum on my face and just having healthy skin is allowing healing. I am reordering this product because I'm addicted to how good the whole skin care line together improves my skin. I feel like the naturally pretty girl in a teen movie lol.
My favorite Paula product
By cjeta
from CT
I love putting this on, it leaves skin feeling great. By far my favorite Paula product. I have really sensitive skin, it gets red so easy and feel like this has helped! I know there's a new redness relief line but honestly not sure if it would be worth switching over, love this one!


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Company Overview of A & A Smart Shopping, Inc.
Company Overview
A & A Smart Shopping, Inc. operates as a wholesaler for candies, groceries, snacks, and beverages. The company also offers its products online. It serves retail stores, organizations, and individual consumers. The company was founded in 1990 and is based in El Monte, California.
1554 Santa Anita Avenue
El Monte, CA 91733
United States
Founded in 1990
Key Executives for A & A Smart Shopping, Inc.
A & A Smart Shopping, Inc. does not have any Key Executives recorded.
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The Adelaidian way to say sure. Used only by people who are never serious.
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Beküldő: Mouche 2006. május 24.
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