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Comparative phylogenies and host specialization in the alder ectomycorrhizal fungi
Mycorrhizal fungi form intimate associations with their host plants that constitute their carbon resource and habitat.
Sporocarps of
Patterns of host specificity and phylogenies of
In the ectomycorrhizal (ECM) symbiosis, the root system of an individual tree is typically colonized by several members of different ECM fungal species, and individual fungi can normally associate with several plants
Based on fossil pollen evidence, the plant genus
After the Quaternary glaciations the circumpolar species
From analysis of mycorrhizae
For the mycorrhizal symbiosis, it is still an open question how associations between plants and fungi arise and how specificity occurs. One way would be geographical isolation of populations leading to a narrowing of host range and allopatric speciation. However, we hypothesize than in highly specialized associations such as the alder-ECM symbiosis, plants exert considerable selective pressure on their fungal symbionts and are major drivers of diversification. This hypothesis was evaluated here by documenting the history of
Strong host-specificity patterns in mutualistic as well as parasitic relationships suggest intuitively a narrow coevolutionary history between symbionts
The fungal lineages,
Host phylogeny and datation
The phylogeny based on the combined data sets from ITS and MatK (Figure
Figure 1
Bayesian cladogram inferred from nuclear rDNA ITS and chloroplastic region MatK sequences of
Bayesian cladogram inferred from nuclear rDNA ITS and chloroplastic region MatK sequences of
Additional file 1
List of tree sequences used in this study. Sequences of
Click here for file
The ITS sequences for most
Additional file 2
List of fungal sequences used in this study. Sequences are either generated by the authors (402 sequences) or downloaded from GenBank or UNITE databases (89 sequences). (1): not a genuine
Click here for file
Because the datasets of the four genes were highly congruent, a combined analysis was conducted on a 2743 bases long alignment, obtained by concatenation of all genes for each sampled morphospecies, with a Bayesian approach (Figure
Figure 2
Phylogenetic reconstruction of the
Phylogenetic reconstruction of the
Figure 3
Phylogenetic reconstruction of the
Phylogenetic reconstruction of the
Figure 4
Phylogenetic reconstructions of the
Phylogenetic reconstructions of the
The/pseudosalabertii clade is coming out as basal lineage amongst sect.
The/luteolofibrillosa lineage appears as a collective species (or as a species complex), represented in Europe by at least two genetically distinct lineages. The former,
The ancestral state in the/luteolofibrillosa lineage is subgenus
In the/badia lineage, three species,
The/umbrina lineage contains
Finally four distinct species that comprise
The monophyletism of both genera
Phylogenetic analysis of the ITS dataset clearly splits
The case of
Collections of
The/lepidotus lineage contains two species that are
All collections of
The two remaining lineages (/omphaliformis and/obscuratus) are more modern than the previous ones, coming out from a species-rich group of small
The/obscuratus lineage is composed of morphologically highly variable and taxonomically confused taxa (Figure
Looking for early speciation events
The ancestral position of subgenus
Recent host-dependent evolution processes
If the hypothesis of co-speciation could explain the basal topology of the oldest
Host shifts but not host extension?
The two hypotheses previously suggested - early co-evolution with
What Corsica tells us about host shifts
The geographic co-expansion of
Corsica is a remarkable exception to this general pattern of host-symbiont association. Thus, host jumping to distantly related hosts appears to be facilitated in Corsica because there are at least three species of fungi that are commonly found under
It is likely that the speciation process by host shift which led to the differentiation of most
The factors driving ECM diversity in terms of speciation processes remain poorly documented, and only a few examples have been satisfactorily investigated. The interactions between alders and ectomycorrhizal fungi appear highly specialized, and as a consequence when hosts undergo certain selection regimes, their symbionts might also take evolutionary steps to maximize their fitness. The evolutionary framework developed in this study gives an alternative to the cyclic-biphasic model developed on
Because coevolutionary events become masked through time via host switching, extinction and duplication, finding empirical evidence for co-speciation (or co-divergence) patterns has proven difficult in many groups of organisms, including classical examples of animal parasites. However, possibly due to the very selective pressure of the host, ECM coevolution appears in
The second element of the historical associations between plants and fungal symbionts is a host-dependent speciation (radiation without host change), suggested marginally
Host shifts from
Although extreme specialization may represent an evolutionary-dead-end, host-dependent speciation seems to have played a more important role than host shift across large phylogenetic distances in the evolution of the studied fungi, as especially illustrated by
Inferences about the evolutionary events of symbionts in the light of phylogenies are sensitive to the information at hand. By adding missing or newly discovered fungal species to the trees, especially from the numerous non-investigated alder species outside Europe, our picture about the details of coevolution or host switching may change. Advancing the work presented here would benefit from additional sampling of the fungi (sporocarps and mycorrhizae), particularly in areas that would introduce new host associations not represented here. Although estimation of the time of divergence of the clades will always be difficult in fungi due to the lack of fossils, what is also required is a comprehensive and well calibrated tree based on numerous molecular divergence rate estimates. Most such data are not available today. A concerted effort is thus necessary for understanding the evolution of
The present study focused on historical events and co-evolutionary relationships in explaining current patterns of host specificity in the
Taxonomic sampling
The four European native species of alders (= five species and subspecies) are listed in Additional file
Most fungal sequences used in this study are derived from extensive sporocarps sampling of
Figure 5
Mapping of sampled sites for sporocarps in Western and Central Europe (for details see Additional file
Mapping of sampled sites for sporocarps in Western and Central Europe (for details see Additional file
DNA extraction, PCR amplification and sequencing
Total DNA was extracted from
Two DNA regions were selected for the present
One to four regions were amplified and sequenced depending on the genus and sample. The DNA regions and primers used for PCR are the nuclear rDNA ITS using the primer set ITS-1F/ITS-4B
Amplifications were carried out in 25 μl reaction containing 0,2 μl of Go
PCR products were loaded onto a 1.25% standard agarose gel for electrophoresis (20 min at 100 W). Gels were stained with ethidium bromide and photographed under ultraviolet light. Unsuccessfully amplified samples were subjected to multiple amplifications at various DNA concentrations. Sequencing was done by MilleGen (Labège, France).
Alignment and phylogenetic analyses
Sequences were manually edited using Sequencher 4.8. Gene Codes (Ann Arbor, MI). They were aligned using MAFFT version6 using the LINS-i method with standard settings
In PhyML, trees were constructed for each DNA region using the most general time-reversible model of nucleotide evolution with Gamma distributed errors on mutation rates (GTR+G) and node support was estimated by using the approximate likelihood-ratio test (alrt), a much faster method for estimating branch support than either the bootstrap or Bayesian posterior probabilities
Modeltest 3.7
Estimation of time divergence in
To estimate divergence times between lineages, the combined data set of ITS and MatK sequences was employed. Rate constancy was tested with a likelihood ratio test
ad int.:
Authors' contributions
JR carried out the molecular phylogenies, and participated in writing of the manuscript as a part of her PhD project. PAM carried out most of the sporocarp samplings and taxonomic identifications, and was deeply involved in the writing of the manuscript along with MG. SM did most of the DNA extractions from sporocarps, the PCRs and the editing of the sequences. MG's contributions are the conception and the coordination of the study, the acquisition and the analysis of the data, and the writing of the manuscript. All authors read and approved the final manuscript.
We thank P. Jargeat and H. Gryta for their comments on earlier versions of the manuscript, F. Chassagne for help with the molecular work, and B. Mouhamadou for the V9 sequences annotation. J. Borovička and M. Berbee are thanked for unpublished information about
Specificity phenomena in mycorrhizal symbioses: community-ecological consequences and practical implications
Evidence from population genetics that the ectomycorrhizal basidiomycete
Internal transcribed spacer sequences from 38 recognized species of
Host specificity in ectomycorrhizal communities: what do exceptions tell us?
Evolution and host specificity in the ectomycorrhizal genus
The systematics of the American species of
Tertiary macrofloras of the Bohemian Massif: a review with correlations within Boreal and Central Europe
Zur Systematik und Variabilität der mitteleuropäischen Erlen (Gattung
Phylogenetics and biogeography of
Molecular phylogeny of
Phytotaxonomical and geobotanical studies on genus
Late Miocene to Early Pliocene vegetation of southern Europe (7-4Ma) as reflected in the megafossil plant record
Chloroplast DNA phylogeography of
Post-glacial re-colonization of European biota
La flore orophile de la Corse: origines, rapports avec celle des Alpes et des montagnes de l'Europe méridionale
Vicariance and dispersal in the alpine perennial
Ectomycorrhizal specificity in the genus
Characterization and comparison of macrofungal communities in an
Characterization of red alder mycorrhizae: a preface to monitoring belowground ecological responses
Ectomycorrhizal and arbuscular mycorrhizal colonization of
Revisiting ectomycorrhizal fungi of the genus
A molecular and phylogenetic analysis of the structure and specificity of
Fungus associates of ectotrophic mycorrhizae
Some aspects of
Ectomycorrhizal fungi of whitebark pine (a tree in peril) revealed by sporocarps and molecular analysis of mycorrhizae from treeline forests in the Greater Yellowstone Ecosystem
Phylogeny of the ectomycorrhizal mushroom genus
A nomenclatural revision of the genus
Röhrlinge und Blätterpilze in Europa - unter der Mitarbeit von Anton Hausknecht (Bolbitiaceae) und P.A. Moreau (
Rediscovery of
Description de quelques espèces d'Agarics ochrosporés
Host islands within the California Northern Channel Islands create fine-scale genetic structure in two sympatric species of the symbiotic ectomycorrhizal fungus
Molecular systematics and biological diversification of
Különböző stressztűrőképességű nagygombanemzetségek Kárpát-medencei leletanyagának molekuláris azonosítása és rendszerezése
Walking the thin line between
Lactarius Pers
Étude sur les lactaires de la sous-section des
Clé monographique du genre
Worlwide phylogeny of
Mycological analysis of
Study of natural hybridization between
Patterns of association between crucifers and their flower-mimic pathogens: host jumps are more common than coevolution or cospeciation
Biology of the ectomycorrhizal genus
Geographic structure in a widespread plant-mycorrhizal interaction: pines and false-truffles
Evidence for strong inter- and intracontinal phylogeographic structure in
Multiple origins of sequestrate fungi related to
A molecular phylogeny of
Biology of the ectomycorrhizal genus
Multiple gene genealogies and species recognition in the ectomycorrhizal fungus
ITS primers with enhanced specificity for basidiomycetes - application to the identification of mycorrhizae and rusts
Improving phylogenetic inference of mushrooms with RPB1 and RPB2 nucleotide sequences (
Development of primer sets to amplify fragments of conserved genes for use in population studies of the fungus
Phylogenetic species delimitation in ectomycorrhizal fungi and implications for barcoding: the case of the
Sequence and secondary structure of the mitochondrial small-subunit rRNA V4, V6, and V9 domains reveal highly species-specific variations within the genus
Molecular evolution of mitochondrial ribosomal DNA in the fungal genus
MAFFT version 5: improvement in accuracy of multiple sequence alignment
A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood
MrBayes: Bayesian inference of phylogeny
Modeltest: testing the model of DNA substitution
Selecting the Best-Fit Model of Nucleotide Substitution
PAUP*. Phylogenetic Analysis Using Parsimony (*and Other Methods)
Phylogenies from molecular sequences: inference and reliability
BEAST: Bayesian evolutionary analysis by sampling trees
Relaxed phylogenetics and dating with confidence
Tracer v1.4
Teasing apart molecular- versus fossil-based error estimates when dating phylogenetic trees: a case study in the birch family (Betulaceae)


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Even though it rained the whole time I was there and crawling with people, it is a magical place and well worth a visit.
image source and source
Labels: architecture, U.K
Welcome to Endless Inspiration. This is the place I share all the things which bring me joy, from a gorgeous interior or a phenomenal piece of architecture, to adventures in the great outdoors and everything in between.
Labels: architecture, U.K
Hi I too love the Sophie conran china.
I only recently discovered it here in Adelaide I'm determined to buy some pieces in celedon.
What a fabulous place Portmeirion is another part of the world too see.
Kind regards
Wow, it never occurred to me that it's an actual place. It is heavenly there and what wonderful photos! Thanks for sharing this Vanya!!
Best photos of Portmeirion I have ever seen, loved looking at them and would love to visit.
Happy Week-end!
It looks like a beautiful village and I do love that porcelain range, xv.
Your blog is soo cute & nice & very tasty!!
Regards from Agneta in Sweden
Hi there from Oz ... have to say your images are wonderful. What a great blog you have.
Hope your having fun over there!:)
It looks wonderful. Is great to see the photo's. Ax
I had to keep checking back that yes, it was actually Wales I was looking at Vanya. Fab pics, lovely to have my mind expanded yet again here @ EI.
Millie ^_^
I'm going to Wales this summer - wow, what lovely photos.
I have Portmeirion dishes and love, love, love them. How interesting that I found your blog at this time -
Just dropped by to say hello and what a lovely blog this is! I visited Portmeirion as a child and was enchanted! Your pics have brought back so many happy memories! Incidentally, did you know the cult TV series, The Prisoner, with Patrick McGoohan was fimed there? Magical!
Have a wonderful weekend!
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Fabric and color of this item may vary in our showroom.
Belfort Furniture offers White Glove in-home delivery and set-up by professionally trained personnel who will unwrap, place, and assemble your furniture in the appropriate room. Delivery is available Tuesday - Saturday. Once your delivery date is scheduled, you will receive a three hour delivery timeframe the day prior to your delivery.
Furniture may be picked up at our warehouse Monday-Saturday from 10AM to 6PM or Sunday from Noon to 5PM. Furniture that is picked-up may require assembly.
For delivery outside of our local metropolitan area, please contact us with your item(s) of interest for a delivery quote! 703-406-7600 or firstname.lastname@example.com
This upholstered, lift top ottoman features storage without compromising style. Couple it with a sectional, reclining sofa, or add it to existing collections to make the best use of your space!
The Daley 41162 Home Theater Lift Top Ottoman by Palliser from Belfort Furniture. We proudly serve the Washington DC, Northern Virginia, Maryland and Fairfax VA area. Product availability may vary. Contact us for the most current availability on this product.
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Hijrah Chocolate Sdn Bhd is a health & beauty company that operating in Shah Alam. We are now looking for interns to be part as our team as detail below :-
Intern in Marketing.
Job Scope
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- Monthly allowance.
- Have opportunity to be absorbed as a permanent staff.
- Required languages :- English & Bahasa Melayu.
- Working hours :- 9.00am – 6.00pm , Weekdays.
- Location :- Seksen 6, Shah Alam.
Internship Duration: 3 months & above
Monthly Allowance: Contact us for allowance enquiry


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This property is no longer available.Search for Available Property.
Lake Limestone, TX Custom Home on Main Lake
1,508 + sq. ft. 3 bed, 2 bath, well maintained custom brick home on slab, built in 1998 on main lake, living room & dining area have a view of the lake, vaulted ceilings, crown molding throughout home, spacious master bedroom has great view of the lake, kitchen & bathrooms have marble counter tops, master bath has shower & separate closets, this house has plenty of closet space, utility room has extra counter space & storage that is just off the kitchen, carpet in living area & bedrooms all other areas are tile, 2015 installed new central air & heat, nice patio area for grilling, entertaining, relaxing & enjoying the beautiful view of the main lake, 30 x 40 metal insulated 4 car detached garage w/workshop has lots of room for storage plus loft for storage or need more room for sleeping a lg. group of family &/or friends, the loft could be closed in for more sleeping quarters w/water available, plus cottage has a/c unit w/nice front porch, landscaped & plenty of mature trees to shade the yard, or week end get away/vacation home, approx. 100 ft. of bulkheaded water front, covered dock for fishing, relaxing &/or watching the children swim
Lake Limestone is a great lake for fun, fishing, boating, water sports or just relaxing. The lake is centrally located approx. 2 to 2.25 hours from Dallas/Ft. Worth, Houston or Austin. The lake is south of Groesbeck, north of Franklin, east of Waco, west of Centerville.
As a Realtor who lives and fishes on Lake Limestone, I can help you with your real estate needs or for more information about Lake Limestone, contact me.
Information furnished is from sources deemed reliable but is not guaranteed by us. This offering is subject to change in price, corrections, errors, and omissions, prior sales or withdrawal without notice.
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off FM 937, turn on LCR 743, turn R on Post Oak Loop, turn L on Pine Ct., turn R on Lakeshore Dr., stay straight property on L
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"Circle Less. Live More": Words To Park By
Streetsblog notes that performance parking also can result in reduced meter costs. The key is not to increase revenue but to ensure one parking space is available per block.
"In a refreshing turn, the San Francisco Municipal Transportation Agency (SFMTA), which runs Muni and manages the streets of San Francisco, has produced an informative and whimsical animated short explaining how their dynamic parking management pilot, SFPark, will work."
SFpark Overview from SFpark on Vimeo.
Thanks to San Francisco Bicycle Coalition News


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Reflect Window and Door offers an extensive line of sliding glass patio door rollers. Choose from nylon or stainless steel ball bearing and tandem rollers with housings for use on all makes and models of sliding patio doors including Truth, Indal, Fleetwood, Alcan, Northrop, Ado, Pacific, Trimview and more. Ask our sliding patio door hardware experts about quantity discounts and our affordable shipping rates!
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The History Of Applied Mathematics And The History Of Society
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Choosing the history of statistics and operations research as a casestudy, several ways of setting the development of 20th century appliedmathematics into a social context are discussed. It is shown that there isample common ground between these contextualizations and several recent research programs in general contemporary history. It is argued that a closer cooperation between general historians and historians ofmathematics might further the integration of the internalist andexternalist approaches within the historiography of mathematics.
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Apr 17, 2004 - 10:56 am
Hi all,
Apr 17, 2004 - 3:50 pm
Hi Judy,
I agree it is a good idea to follow your body's message about how much to take on, etc. My husband could in no way work for the first few months of chemo and then radiation. However, when he had recovered from the combo and was getting chemo once a week for three weeks and then a week off, he went back to work half days and it did him the world of good mentally. It gave him something other than his illness to concentrate on.
So enjoy this time of "rest" but do make sure you keep your mind occupied on something other than cancer. I am the caregiver and the first thing I do when I go online, is check this board and another one....sometimes I wonder if I am totally obsessed!! So to focus on other aspects of life is good! I need to listen to myself!
Best, Alison
Apr 17, 2004 - 9:48 pm
Hi Judy. I remember when I was part-way through my chemo, my dr. 'strongly advised' me to take more sick leave. I was so relieved! I did a little bit of work from home (my job is flexible that way) - but only as I felt. For me, the chemo-fatigue did get worse, not better, as time progressed. I tried to have a nap every day! and certainly a 'rest'. It sounds like you have made a good decision. Best of luck with the rest of the chemo
Apr 17, 2004 - 10:42 pm
Hi Judy- Listen to your body. If you are getting that fatigued, it is a good thing to take the time off. Just the fact that you feel so relieved having decided to do this is an indication that you needed to do it.
I right now am in the opposite situation and going a bit crazy in that I am feeling fine. I was planning to work pretty much most of this month with the exception of a couple days off for chemo. However I've had some blood in my urine which have resulted in 7 more doctor CT, ultrasound appointments than anticipated..Of course all of these are scheduled on separate days at their whim, on the days that are most useful for me to be at work. GRRRR!
Sometimes it is hard to run your life anything close to normal along with this disease, let alone with kids and the rest of the family to look after.
Hope you feel better soon.
Apr 18, 2004 - 1:53 am
Hi Judy:
Apr 18, 2004 - 7:20 am
Good for you Judy!
Apr 18, 2004 - 9:59 am
Hi Guys, Thanks for your support.
Apr 18, 2004 - 10:40 pm
Glad to hear you have made a decision and are doing ok. I was fortunate in that I didn't have to work, but if I had needed to depend on my job, I don't know how I would have done it. I admire all of your who have kept your jobs and gone through treatment at the same time. You are remarkable. I am feeling pretty good now that I am 9 months off of chemo and 15 months from my diagnosis.
You are all such a special group of friends. I think of your often and hold you in my prayers.


text:
The Administration, Faculty and Staff of Ledyard Charter School share one goal: to educate each student by capitalizing on his or her individual strengths.
The Learning Community at Ledyard Charter School will strive to:
- discover meaning in every experience, endeavor, act, and challenge;
- build and maintain relationships, which are crucial in the development of every person;
- appreciate and embrace work not for grades but as a means to understanding, discovery, awareness, empathy and the rewards that are reaped from stretching oneself;
- harness our personal strengths to make a positive impact on the world;
- understand that Education serves as a gateway for life long success;
- unearth and create the means to better ourselves and the lives of others ~ oppose prejudice and intolerance, empowering ourselves and our communities with the knowledge that we can achieve more together, and that each person is valuable;
- teach as we learn, welcoming the community into the fold as we strive to better our lives for ourselves, those in the Upper Valley, and citizens around the globe; and
- live adventurously, as did our namesake, John Ledyard, who spent four months living (and learning) among the Iroquois as a college ambassador.
The Ledyard Charter School Board of Trustees is comprised of ten members of the Upper Valley who are committed to the success of LCS by serving to uphold the mission of the school and act as the responsible agents for school and state accountability requirements.
2016-17 LCS Board of Trustees:
- Chris Rhim, Chair
- Evan Leary, Treasurer
- Elizabeth Bailey, Esq., Secretary
- Dr. Michael Harris
- Dr. Lauren Morando-Rhim
- Travis Bill
- Thea Crawford
- Eric Janisch
- Brett Mayfield
- Amos Kornfeld
LCS Board Meeting Dates for 2016-17 School Year
Executive Board meetings are held at LCS and are open to the public. Come join us !!! They are held on the 2nd Tuesday of every month, from 6 p.m. to 8 p.m. (dates subject to change).
- August 9, 2016
- September 13, 2016
- October 11, 2016
- November 8, 2016
- December 13, 2016 (will be held in private room at Three Tomatoes)
- January 10, 2017
- February 14, 2017
- March 14, 2017
- April 11, 2017
- May 9, 2017
- June 13, 2017 (cancelled)
- Board Retreat at the Montshire Museum, Norwich, VT – June 21st & 22nd – 6 to 8 pm
Below is a link to our Board Minutes page, which contains both Draft and Approved Minutes.
Executive Director
Mr. John Higgins
Executive Administrative Assistant
Lisa Swett
Student Support Coordinator
Laura Carroll
English & Art Teacher
Ms. Wendy Tucker
Social Studies & Physical Ed Teacher
Terence Relihan
Math & Science Teacher
Chris Allen
Marta Bird
Para-Educator (Behavior Coach)
Alison Whitehead


text:
|Publication number
|Publication type
|Application number
|Publication date
|Dec 31, 2002
|Filing date
|Aug 31, 1998
|Priority date
|Jul 16, 1997
|Fee status
|Also published as
|Publication number
|John W. Meadows, Glenn R. Edwards, Samuel A. Marquiss, Amer El-Hage, Douglas N. Modlin
|Original Assignee
|Ljl Biosystems, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (162), Non-Patent Citations (55), Referenced by (19), Classifications (39), Legal Events (9)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a continuation of the following patent applications, each of which is incorporated herein by reference: U.S. patent application Ser. No. 09/062,472, filed Apr. 17, 1998, now U.S. Pat. No. 6,071,748; PCT Patent Application Ser. No. PCT/US98/14575, filed Jul. 15, 1998, now abandoned; U.S. patent application Ser. No. 09/118,141, filed Jul. 16, 1998, now U.S. Pat. No. 6,313,960; U.S. patent application Ser. No. 09/118,310, filed Jul. 16, 1998, now U.S. Pat. No. 6,033,100; and U.S. patent application Ser. No. 09/118,341, filed Jul. 16, 1998, now U.S. Pat. No. 6,025,985.
This application, directly and/or through its parent applications, is based upon and claims benefit under 35 U.S.C. �119 of the following U.S. Provisional Patent Applications, each of which is incorporated herein by reference: Ser. No. 60/052,876, filed Jul. 16, 1997; Ser. No. 60/059,639, filed Sep. 20, 1997; Ser. No. 60/063,811, filed Oct. 31, 1997; Ser. No. 60/072,499, filed Jan. 26, 1998; Ser. No. 60/072,780, filed Jan. 27, 1998; Ser. No. 60/075,414, filed Feb. 20, 1998; Ser. No. 60/075,806, filed Feb. 24, 1998; Ser. No. 60/082,253, filed Apr. 17, 1998; Ser. No. 60/084,167, filed May 4, 1998; Ser. No. 60/085,335, filed May 13, 1998; Ser. No. 60/085,500, filed May 14, 1998; Ser. No. 60/089,848, filed Jun. 19, 1998; Ser. No. 60/094,275, filed Jul. 27, 1998; Ser. No. 60/094,276, filed Jul. 27, 1998; and Ser. No. 60/094,306, filed Jul. 27, 1998.
This application incorporates by reference the following U.S. patent application Ser. No. 09/144,575, filed Aug. 31, 1998, now U.S. Pat. No. 6,159,425.
The invention relates to a device for high-throughput screening. More particularly, the invention relates to a device for automatically feeding microplates into an analyzer for high-throughput screening.
High-throughput screening instruments (or analyzers) are critical tools in the pharmaceutical research industry and in the process of discovering and developing new drugs. High-throughput analyzers are used to assess the efficacy of candidate drug compounds. Dramatic increases in the number of these compounds and in the number of targets against which they may be directed have created a bottleneck in the development of new drugs and a need for analyzers that can operate with a high degree of analytical flexibility and speed. Analytical flexibility and speed are necessary because high-throughput applications may involve repeating the same operations hundreds of thousands of times, greatly magnifying even the smallest shortcomings.
One way to increase speed and analytical flexibility is to house a variety of small-volume samples in a single container. Toward this end, high-density containers known as microplates have been developed. Microplates are generally rectangular containers that include a plurality of sample wells for holding a plurality of samples. Microplates enhance speed by reducing transit time between samples and reduce cost by employing small amounts of reagents. Unfortunately, microplates also have a number of shortcomings. For example, microplates do not conform to any exact standard, so that their size, shape, and construction materials may vary, depending on vendor or batch. In addition, microplates may vary from opaque to transparent, so that analytical approaches developed for some microplates will not work for other microplates. Moreover, preferred microplates may differ, depending on application. Furthermore, microplates may allot only a small volume for each sample, so that signal is reduced and sample is more easily spilled during transit.
Another way to increase speed and analytical flexibility is to use robots and other devices to automate high-throughput screening procedures. For example, robots permit analyzers to run 24 hours a day. Unfortunately, current robotic systems have a number of shortcomings. For example, robots commonly are used to deliver samples to an analyzer for analysis. However, the robot typically must make separate trips to drop off a sample container, such as a microplate, before analysis, to retrieve the sample container after analysis, and then to drop off another sample container for analysis. In this approach, the analyzer is idle during the time that the robot is retuning the analyzed microplate and bringing the new microplate. As time and the number of sample containers analyzed increases, the total down time due to robotic transport may become quite significant.
Another way to increase speed and analytical flexibility problem is to permit manual or automated feeding of sample containers. Unfortunately, switching between manual and automated feeding modes with current analyzers has a number of shortcomings. For example, automated microplate feeding systems may not permit manual feeding while the automated feeder is connected to the analyzer. To use such an analyzer in a manual mode, the automatic feeder must be disconnected.
The present invention addresses these and other shortcomings by providing a sample feeder that includes (1) a first station that receives and initiates transport of a sample container into an analyzer for analysis, (2) a second station where the sample container is handed off to a transporter that carries the sample container to and from an examination site inside the analyzer, and (3) a third station that collects the sample container after examination. The sample feeder may include a singulation mechanism positioned at the first station and configured to separate a sample container from a stack of sample containers for transport to the analyzer, and/or a stacking mechanism positioned at the third station and configured to add a sample container to a stack of sample containers. The sample feeder further may include a preprocessing bin positioned at the first station for holding a stack of sample containers to be analyzed, and/or a postprocessing bin positioned at the third station for holding a stack of sample containers after they have been analyzed.
The invention also provides a sample feeder that includes (1) a lifter configured to raise or lower a sample container relative to the bottom of a stack of sample containers, and (2) at least one latch having a pick portion, the latch being mounted so that the pick portion moves in and out of gaps between adjacently stacked sample containers in response to up and down movement of the lifter. The lifter and latch may be designed to remove a single sample container from the bottom of a stack of sample containers, or to add a single sample container to the bottom of a stack of sample containers. The latch may include a pick portion that is urged toward the bottom of the stack by gravity, a spring, or other mechanisms.
The invention also provides a sample feeder that includes (1) a lifter configured to impart a raising or lowering motion to a sample container to transfer the sample container to or from a stack of sample containers, and (2) a drive motor configured to generate a driving motion, wherein the lifter includes a cam operatively connected to the drive motor and configured to convert the driving motion into the raising or lowering motion.
The invention also provides an automated analyzer system that includes (1) an analyzer unit having an internal examination site, and (2) first and second external loading stations, the first external loading station configured to receive a sample container before analysis, the second external loading station configured to receive the sample container after analysis. The automated analyzer system may include a robot programmed to deliver a sample container to the first external loading station, and to retrieve a different sample container from the second loading station in the same trip.
The invention will be understood more readily after consideration of the drawings and the detailed description of the invention that follow.
FIG. 1 is a partially exploded perspective view of an analyzer, showing a transporter and sample feeder constructed in accordance with the invention.
FIG. 2 is a perspective view of the top of a transporter constructed in accordance with the invention.
FIG. 3 is a perspective view of the bottom of the transporter shown in FIG. 2.
FIG. 4 is a partial cross-sectional view of the transporter shown in FIGS. 2 and 3, taken generally along the line 4—4 in FIG. 3.
FIG. 5 is a perspective view of a base platform and associated drive mechanisms for moving a transporter along X and Y axes relative to the base platform.
FIG. 6 is a perspective view of a sample feeder constructed in accordance with the invention, with bins removed so that internal mechanisms of the sample feeder can be viewed.
FIGS. 7A and 7B are cross-sectional views through a first (input) station of the sample feeder shown in FIG. 6, taken generally along the line 7AB—7AB in FIG. 6 and showing latch and lifter cooperation to remove a microplate from the bottom of a stack.
FIGS. 8A and 8B are cross-sectional views through a third (output) station of the sample feeder shown in FIG. 6, taken generally along the line 8AB—8AB in FIG. 6 and showing latch and lifter cooperation to add a microplate to the bottom of a stack.
FIG. 9 is a side elevation view of a lifter from the sample feeder shown in FIG. 6.
FIG. 1 shows a high-throughput luminescence analyzer 50 constructed in accordance with the invention. Components of the analyzer are maintained in a housing 100, both for organization and for protection. Housing 100 is substantially rectangular and includes light-tight exterior top 102, side 103 a-d, and bottom walls 104 that reduce background in luminescence measurements. The walls may include vents 106 to facilitate air flow through the analyzer and a transporter port 107 for sample input/output. Housing 100 also may include feet 108 to support the analyzer and to permit air flow between the analyzer and any support structure on which the analyzer is placed.
Analyzer 50 is substantially automated. The analyzer is designed so that user interactions occur primarily through a control unit 110, an electronic input/output panel 112, and a break-out box (not shown), each of which supports a variety of input/output functions. The analyzer also is designed so that sample input/output occurs primarily through a transporter/stage 114 and an optional sample feeder 116.
Transporter 114 generally comprises any device for supporting a sample container. In analyzer 50, transporter 114 moves between the interior and exterior of the analyzer, and may be used alone or together with sample feeder 116 for sample input/output.
Sample feeder 116 generally comprises any device for automatically processing multiple samples. In analyzer 50, sample feeder 116 includes a first (input) station 118 for holding sample containers to be read, a third (output) station 120 for holding sample containers that have been read, and a second (direct transporter access) station 122 for inputting or outputting sample containers that bypasses the input and output stations. Input and output stations 118, 120 accommodate preprocessing and postprocessing sample containers bins 124, 126 that hold and organize stacks of sample containers before and after reading, respectively. Sample feeder 116 also may include a barcode reader 128 for automatically identifying labeled sample containers.
The sample container generally comprises any container for holding at least one sample. Preferred sample containers include microplates. Other suitable sample containers include any sample containers having a shape and rigidity suitable for processing in an analyzer, such as slides or supported gels.
FIGS. 2-5 show a stage, which generally comprises any mechanism for supporting a composition in a sample container for analysis by the analyzer. In analyzer 50, the stage includes a transporter 200 and base platform 300.
FIGS. 2-4 show transporter 200, which includes a transporter body 202 and substantially parallel first and second transporter flanges 204 a,b that extend outward from transporter body 202. First and second transporter flanges 204 a,b terminate in first and second transporter extensions 206 a,b that turn in toward one another without contacting one another. Transporter extensions 206 a,b may be joined by a connector portion 207. Transporter body 202, flanges 204 a,b, and extensions 206 a,b lie substantially in a plane and define a transporter cavity 208 that is larger than the expected peripheral dimension of any sample containers which the transporter is intended to support. The shape of this cavity is chosen to accommodate the shape of the preferred sample containers. In analyzer 50, cavity 208 is generally rectangular to accommodate generally rectangular sample containers, such as microplates. In analyzer 50, long sides of the rectangular sample container are positioned against flanges 204 a,b.
Transporter 200 includes a shelf structure and associated frame structure for supporting a microplate or other sample container. For example, transporter shelves 210 along portions of body 202, flanges 204 a,b, and extensions 206 a,b form a shelf structure that supports the bottom of the sample container. The shelf structure also could include other support mechanisms, such as pins or pegs.
The transporter also includes an automatic sample container positioning mechanism 220 for positioning sample containers precisely and reproducibly within cavity 208. Mechanism 220 includes Y and X axis positioning arms 222 a,b that contact the sample container to control its Y and X position, respectively. Here, a Y axis is defined as generally parallel to transporter flanges 204 a,b and an X axis is defined as perpendicular to the Y axis and generally parallel to transporter extensions 206 a,b. Other coordinate systems also can be defined, so long as they include two noncolinear directions.
Y-axis positioning arm 222 a lies substantially within a channel 224 in body 202. Y-axis positioning arm 222 a includes a rod 226 a which is bent at substantially right angles to form three substantially coplanar and equal-lengthed segments. A first end segment 228 a of rod 226 a terminates near cavity 208 in a bumper 232 for engaging a sample container. A second end segment 234 a of rod 226 a terminates away from cavity 208 in an actuator tab 236 a for controlling movement of arm 222 a. Actuator tab 236 a is bent away from body 202. First and second end segments 228 a, 234 a are substantially parallel. A middle segment 238 a of rod 226 a connects the two end segments at their nontabbed ends 240, 241. An X-axis biasing spring 242 a having first and second spring ends 244, 248 is slipped over rod 226 a. First spring end 244 is held to second end segment 234 a of rod 226 a by a clamping-type retaining ring 250. Second spring end 248 rests against a rod bearing 252. The Y-axis biasing spring extends substantially parallel to first and second end segments 228 a, 234 a. The force from spring 242 a is transmitted to rod 226 a by the clamping action of retaining ring 250.
X-axis positioning arm 222 b also lies substantially within channel 224 in body 202 and is similar to Y-axis positioning arm, except that (1) first end segment 228 b is longer and middle segment 238 b is shorter in rod 226 b of the X-axis positioning arm than in rod 226 a of the Y-axis positioning arm, (2) first end segment 228 a terminates in a lever tab 253 in the X-axis positioning arm rather than in bumper 232 in the Y-axis positioning arm, and (3) the two rods bend in opposite directions between first end segments 228 a,b and second end segments 234 a,b.
X-axis positioning arm 222 b is connected via lever tab 253 to an X-axis positioning lever 254 that lies along transporter flange 204 b. X-axis positioning lever 254 includes first and second lever projections 256, 258 and is pivotally mounted about a lever pivot axis 259 to transporter 200 near the intersection of body 202 and flange 204 b. First lever projection 256 is substantially perpendicular to flange 204 b and abuts lever tab 230 b on X-axis positioning arm 222 b for actuating the positioning lever. Second lever projection 258 also is substantially perpendicular to flange 204 b and includes an edge 260 for contacting a sample container.
Transporter 200 functions as follows. For loading, the transporter occupies a loading position substantially outside a housing. In this position, actuator tabs 236 a,b abut an actuator bar 270, shown in FIG. 5. In addition, biasing springs 242 a,b are compressed, and bumper 232 and second projection 258 having edge 260 are pulled out of cavity 208. A person, robot, or mechanical stacker then can place a sample container into cavity 208 so that the bottom of the sample container rests on shelves 210. Cavity 208 is larger than the sample container to facilitate this placement and to accommodate variations in sample container size.
In some configurations, connector portion 207 may be removed, such that transporter 200 has an open end. This open end permits a microplate transfer device to enter cavity 208 and the generally rectangular area of the holder. The microplate transfer device may, after moving into the generally rectangular area, move down relative to transporter 200, thereby gently placing the microplate into the generally rectangular area.
For reading, the transporter must deliver the sample container to an examination site inside the housing. In this process, the transporter moves parallel to second end segments 234 a,b, and actuator tabs 236 a,b disengage actuator bar 270. Biasing spring 242 a pushes Y-axis positioning arm 222 a toward cavity 208. Bumper 232 engages the sample container and pushes it away from body 202 until it abuts extensions 206 a,b. Biasing spring 242 b pushes X-axis positioning arm 222 b toward cavity 208. Edge 260 of second projection 258 engages the sample container and pushes it away from flange 204 b until it abuts flange 204 a.
As long as the sample container is placed in any position on the lower guide shelves, it may be positioned (registered) precisely and reproducibly against a reference corner 272 within cavity 208 under the action of both positioning arms. Biasing springs 242 a,b can be chosen to have different strengths, so that the X-Y positioning action is performed less or more forcefully. In analyzer 50, middle segment 238 b and first lever projection 256 of positioning lever 254 can be varied in length to cause registration to occur in series, first along the X-axis or first along the Y-axis, and second along the Y-axis or second along the X-axis, respectively. For example, reducing the length of middle segment 238 b and reducing the length of projection 256 will cause registration to occur first in the X-axis, and second in the Y-axis.
Positioning lever 254 and bumper 232 are retracted when body 202 of the automatic microplate positioning transporter is moved to the eject position by the X,Y stage. Thus, the microplate is placed on transporter shelf 210 only when the lever and bumper are retracted. Two springs 242 a,b are attached to the rods, which run along the length of the transporter body and end perpendicular to the body. When the transporter is moved to the eject position, the two perpendicular ends of the rods encounter a stop 270, which consists of a rectangular structure located above and parallel to the body. The stop prevents the two perpendicular ends of the actuators, and thus the actuators, from moving with the transporter body. This causes the two springs to contract, changing the position of the transporter arms and increasing the amount of room for the microplate. The microplate then can be placed on the guide shelf of the body. When the body of the automatic microplate positioning transporter is moved back away from the stop, the two perpendicular ends of the actuators no longer are blocked, which allows the actuators, springs, and transporter arms to move into their original position. The expansion of the springs pushes the microplate exactly into position, as defined by the reference corner.
Thus, components of transporter 200 act as first and second releasable clamp mechanisms. The first releasable clamp mechanism applies a force against a first (e.g., Y or X) side of the microplate, thereby securing the microplate in the holder. The second releasable clamp mechanism applies a force against a second (e.g., X or Y) side of the microplate, thereby securing the microplate in the holder from two sides. These clamp mechanisms may sandwich a microplate between the positioning arms and opposing portions of the frame structure, such that the positioning arms function as pushers and the opposing portions of the frame structure function as bumpers for the clamp mechanisms.
The invention provides a method of automatically feeding microplates in and out of an analyzer. The method comprises (1) automatically delivering a microplate just outside an opening to the analyzer, (2) moving a gripping device from inside the analyzer, through the opening, to a location immediately below the microplate; and (3) gently placing the microplate onto the gripping device. The method further may comprise clamping the microplate in the holder by applying a first force against a first side of the microplate, applying a second force against a second side of the microplate, and/or serially performing the clamping steps.
FIG. 5 shows a base platform 300 with drive mechanisms for moving a transporter 302 between loading and examination positions or sites. As previously described, transporter 302 includes flanges 304 a,b defining a cavity 306 for receiving and gripping a microplate (not shown). A Y-axis drive mechanism 307 is provided for moving transporter 302 along a first track 308 relative to the Y-axis, from a loading position 310 toward an examination position 312. An X-axis drive mechanism 313 is provided to move transporter 302 to examination position 312 along a second track 314 relative to the X-axis.
In operation, a microplate is loaded in transporter 302 at loading position 310. Transporter 302 is driven toward the examination position by Y-axis drive mechanism 307. A sensor (not shown) detects the presence of the sample container. The analyzer may be configured automatically to read the microplate once the sensor detects its presence, or the analyzer may be configured to signal the system controller through a data port that a microplate has been received and that the analyzer is ready to accept a command to begin reading. The X- and Y-axis drive mechanisms then operate together to align selected microplate wells with an optical axis, substantially parallel to a Z-axis, along which a sensed volume for luminescence detection may be defined by optical components contained in one or both of a top and bottom optics head positioned above and below base platform 300, respectively.
Transporter 300 thus may function both as a sample delivery device in and out of the analyzer, and as a moveable stage for supporting the sample container at the examination site. The cavity in the transporter permits analysis to be carried out from below the holder, when the transporter is functioning as a stage at the examination site.
X- and Y-axis drive mechanisms 307 and 313 may be controlled by a high-performance motion control system that maximizes throughput while minimizing detection errors. A preferred high-performance control system includes precision five-phase stepper motors that employ encoder feedback to move the microplate quickly and accurately to each read position. The control system may optimize the acceleration/deceleration profiles of the microplate to minimize shaking of fluid within the microplate, for example, by minimizing "jerk" (the time rate of change of the acceleration of the microplate). Alternatively, the control system may increase throughput by moving plates more quickly, if higher variation in results due to increased shaking and settling time may be tolerated.
FIGS. 6-8 show a sample feeder 400, which generally comprises any mechanism for automatic processing of multiple sample containers. Sample feeder 400 enhances convenience by reducing the amount of human intervention required to run the analyzer. Sample feeder 400 also enhances throughput by reducing the amount of time required to process multiple sample containers.
Generally, sample feeder 400 operates as follows. Before reading, a robot (1) removes a sample container from the bottom of an input stack of sample containers at an input station, (2) transports the sample container to a direct transporter access station, and (3) transfers the sample container to a transporter. After reading, the robot (1) takes the sample container from the transporter, (2) transports the sample container to an output station, and (3) transfers the sample container to the bottom of an output stack of sample containers. Sample feeder 400 requires only two motors to provide these functions with high throughput (˜5 seconds for load and unload time).
FIG. 6 shows sample feeder 400 with its preprocessing and postprocessing bins removed, so that internal mechanisms can be viewed. A microplate 402 is loaded from the bottom of a stack of microplates in the input bin into a first (input) station 404. Microplate 402 then is transported on a tray (not shown) to a second (direct transporter access) station 406, where the microplate is handed off to a transporter (not shown). The transporter transports microplate 402 generally along an axis 408 to an examination site inside the analyzer. After analysis, the transporter transports microplate 402 back along axis 408 generally in the opposite direction to second station 406. Microplate 402 then is handed back to the tray, and transported to a third (output) station 410, where the microplate is added to the bottom of a stack of microplates in an output bin.
In analyzer 50, a first linear path defined by axis 408 connects the examination site to the second station, and a second linear path connects the first, second, and third stations, wherein the first linear path is substantially perpendicular to the second linear path. However, analyzer 50 also may have other configurations. For example, the examination site and the first, second, and third stations may all be positioned along a single substantially linear path.
In input station 404, a combination of two lifters and four latches cooperate to singulate or pick a single microplate from the bottom of a stack. (These lifters are concealed by microplate 402 in FIG. 6.) Latches 412 have pick portions that extend into the cavity of first station 404 and support a stack of microplates. Latches 412 are disposed toward the microplates by configuring the latch to have a center of gravity above and inward relative to a pivot point. As the lifters are raised in the input station, the pick portions of the latches are pushed out of the way, so that the microplate can be supported and lowered by the lifters. After one microplate has passed below the latch, latches 412 move back into a supporting position relative to the remainder of the stack.
In output station 410, a different latch configuration is employed. Latches 414 are urged inward toward the microplates by a spring (not shown). When lifter 416 lifts a microplate against latches 414, the microplate pushes the latches out of the way. After one microplate has passed above the latch, latches 414 move back into a supporting position relative to the remainder of the stack.
FIGS. 7A and 7B show how input station 404 operates. FIG. 7A shows microplate 402 as it is being picked up at input station 404 prior to analysis. Lifters 418 have moved up through holes in tray 420 to contact the bottom of microplate 402, and in the process have pushed latches 412 out of the way. FIG. 7B shows the same structures as FIG. 7A, except that lifters 418 have dropped, thereby lowering microplate 402 onto tray 420 for transport to the analyzer. Pick portions of latches 412 have moved back into the cavity to support the remainder of the stack.
FIGS. 8A and 8B show how output station 410 operates. FIG. 8A shows microplate 402 after it has been delivered to output station 410 following analysis. Lifters 416 then move through holes in tray 420 to raise microplate 402 toward a stack of microplates in the output bin (not shown). FIG. 8B shows the same structures as FIG. 8A, except that lifters 416 have raised microplate 402 past latches 414. Latches 414 are spring biased toward the cavity of third station 410. As lifters 416 raise microplate 402, latches 414 are pushed out of the way by the outer contour of microplate 402. Once microplate 402 is above latches 414, the latches return to their inward position to support the stack of microplates in the output bin. Lifters 416 then retreat downward completely out of the holes in tray 420, so that the tray can translate back to input station 404 to collect another microplate for delivery to the analyzer.
FIG. 9 shows how lifter 416 operates. Generally, the lifter comprises any mechanism configured to raise or lower a sample container. Lifter 416 is substantially rectangular and includes top 422, side 423, and bottom 424 walls. Each of an opposed pair of side walls 423 includes two sloped drive channels 426, which function as cams, and a vertical guidance channel 428. In sample feeder 400, pins are inserted into drive channels 426 and guide channel 428. In alternative embodiments, pins and channels may be replaced with other components, including ridges, bearings, or rollers. Pins inserted into drive channels 426 are connected to a drive motor, which moves the pins through drive channels 426 between a top position A nearer top wall 422 and a bottom position B nearer bottom wall 424. The pins move horizontally along a line 430, so that the pins push against a side 432 of drive channels 426, urging lifter 416 to move both horizontally and vertically. Pins inserted into guidance channels 428 are connected to relatively fixed portions of sample feeder 400, preventing horizontal motion, but permitting vertical motion, so that lifter 416 only moves vertically. As the pin moves between positions A and B, the pin moves a horizontal distance H and a vertical distance V. It is the vertical displacement that creates the raising and lowering motions. H and V may be optimized for particular sample containers and travel distances; in sample feeder 400, H and V are optimized for microplates and are approximately 10 cm and 3.5 cm, respectively. Lifter 416 is raised when the pin is near position A, and lifter 416 is lowered when the pin is near position B.
In use, the drive motor moves the pins horizontally at a substantially uniform rate; consequently, the slope of drive channel 426 determines the mechanical advantage and the rate of vertical motion. Near positions A, B, and an intermediate position C, the slope of drive channel 426 is substantially zero, so that there is substantially no vertical motion. Stated differently, near positions A, B, and C, a preselected vertical position corresponds to a range of horizontal positions. This configuration makes the vertical position relatively insensitive to motor precision or manufacturing tolerance, because the lifter will be at the same vertical position whenever it simply is near positions A, B, or C. Between positions A and C, and between positions B and C, the slope of drive channel 426 is nonzero, so that there is vertical motion. The slope is largest (approximately 30�) between positions A and C, so that the lifter raises and lowers relatively rapidly when it is farthest from the bottom of the stack of sample containers. The slope is smallest (approximately 15�) between positions B and C, so that the lifter raises and lowers relatively slowly when it is nearest to the bottom of the stack of sample containers.
The drive motor generally comprises any mechanism configured to generate a driving motion. The drive motor used in sample feeder 400 is a stepper motor, which generates a constant torque. Generally, stepper motors and cams provide alternative mechanisms for performing the same function, in this case, generating a varying rate of motion. However, pairing a stepper motor and cam together in the invention provides several advantages. In particular, the cam provides mechanical advantage and positional insensitivity, and permits the stepper motor to be run at a constant, optimal speed. If the stepper motor were used alone, an electronic control system would be necessary to vary raising and lowering speed. Conversely, if the cam were used alone, with a nonstepper motor, an electronic control system with feedback control would be necessary to vary raising and lowering speed.
Together, the lifters and latches form a singulation mechanism configured to separate a microplate (or other sample container) from a stack of microplates in the down-stacking or input operation. This mechanism has inherently low sensitivity to the exact size, shape, construction material, and surface finish of the microplate. As described, the invention may include four inwardly sloping, tapered (or angled) latches that cause the stack of microplates to self-center within the microplates input area to accommodate both relatively small and large microplates sizes. Also as described, the invention may include a feature that causes the microplates to drop gently when the singulation mechanism disengages from the edges of the microplates, thus allowing the microplates to drop onto the lifter mechanism support structure, which lowers the microplates to the tray without spilling fluid from the wells.
The down-stacking latches pivot on pins and are actuated by the lifter mechanism so as to retract when the lifter mechanism rises, thereby releasing the bottom microplate from the stack and allowing it to drop softly onto the lifter. When the latches retract, they pivot on their support pins such that their centers of gravity are offset. Consequently, when the lifter mechanism is lowered, the latches will be activated by gravity to return to their nonretracted or extended state, thereby preventing the next microplates in the stack from dropping as the lifter mechanism is lowered. Because the offset in the center of gravity of the latches is only enough to cause them to return to their extended position, they press only very lightly on the edges of the microplate as it drops. Because the ends of the latches are polished smooth, they exert only a small frictional force on the edges of the microplates so as not to cause the microplate to tilt or otherwise hang up as the lifter mechanism is lowered and the microplate is placed on the tray.
Together, the lifters and latches also form a stacking mechanism configured to add a microplate to a stack of microplates. Generally, the up-stacking mechanism resembles the down-stacking mechanism. The lifter mechanism raises the microplate by a fixed amount, thereby causing it to pass by four spring-loaded latches, which retract as the microplate is raised by the lifter. Once the bottom of the microplate is above the top of the latch, the latches are released, and a spring on each latch causes the latch to extend under the microplate. The lifter mechanism then is lowered, causing the microplate to be captured by the now extended latches. The up-stacked microplate thus is added to the bottom of the output stack.
Sample feeder 400 also may employ alternative singulation mechanisms. For example, singulation mechanisms may (1) take microplates from the bottom of the stack in the input station and add microplates to the bottom of the stack in the output station, as above, (2) take microplates from the bottom of the stack in the input station and add microplates to the top of the stack in the output station, (3) take microplates from the top of the stack in the input station and add microplates to the bottom of the stack in the output station, or (4) take microplates from the top of the stack in the input station and add microplates to the top of the stack in the output station.
Sample feeder 400 permits a robot to deliver a sample container to the input station and to retrieve a different sample container from the output station, both in the same trip. This feature is known as "process compression" and reduces robot hand travel in servicing analyzer 50. For example, if there were only one loading station (e.g., the transporter), the robot would have to remove the analyzed microplate before delivering the unanalyzed microplate. Thus, process compression replaces two separate robot movements with one robot movement. Sample feeder 400 may be configured so that the input and output stations can hold a microplate to facilitate process compression.
Sample feeder 400 is designed to be flexible. The input and output stations can accommodate a variety of commercially available microplates and are large enough to allow microplates to be placed in them by a robot or a human hand. Suitable microplates typically have 96 or 384 wells, but other configurations also can be accommodated. The input and output stations also can accommodate a variety of commercially available preprocessing and postprocessing microplate bins for holding a stack of microplates before and after analysis, respectively. Preprocessing bins may be removed from the input station and replaced with another preprocessing bin containing a new stack of microplates with samples to be analyzed. Similarly, postprocessing bins positioned may be removed from the output station and replaced with another postprocessing bin to receive a new stack of microplates with samples that have been analyzed. Microplate bins may be used with other robotics to dispense, wash, and read without restacking microplates. Suitable microplate bins typically can accommodate 0-60 microplates.
Sample feeder 400 also may include a barcode reader, as shown in FIG. 6, which can be used automatically to identify labeled microplates. The barcode reader 434 preferably is positioned in either of two positions adjacent direct transporter access station 406; these positions permit barcode reader 434 to read barcodes mounted on the long edge or the short edge of microplates. Barcodes are read when sample feeder 400 moves the microplate from input station 404 to direct transporter access station 406. Barcodes cannot be read when microplates are delivered directly to the direct transporter access station 406. Barcode reader 434 can be programmed to decode a variety of symbologies, including SPC (EAN, JAN, UPC), Code 39 (3-43 digits), Codabar (3-43 digits), Standard 2 of 5 (3-43 digits), Interleaved 2 of 5 (4-43 digits), Code 93 (5-44 digits), and MSI-Plessey (4-22 digits), among others. Information obtained from the barcode can be used for various purposes. For example, the barcode can be used to name the report file. The barcode also can be used to convey instructions to the analyzer relating to required changes in assay mode or optics configuration.
Accordingly, while the invention has been disclosed in its preferred form, the specific embodiment thereof as disclosed and illustrated herein is not to be considered in a limiting sense, because numerous variations are possible and no single feature, function, or property of the preferred embodiment is essential. The invention is to be defined only by the scope of the issued claims.
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|U.S. Classification
|73/864.81, 422/63
|International Classification
|Cooperative Classification
|European Classification
|Nov 4, 1998
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text:
BG Advanced Product Marketing Manager M/W
{[ sinceDate() ]}
Site internet: http://www.valeo.com/fr.html
BG Advanced Product Marketing Manager M/WSite presentation
Valeo is an automotive supplier, partner to all automakers worldwide. As a technology company, Valeo proposes innovative products and systems that contribute to the reduction of CO2 emissions, the improvement of vehicle performance and to the development of intuitive driving. In 2015, the Group generated sales of €14.5 billion and invested over 10% of its original equipment sales in research and development. Valeo has 134 plants, 17 research centers, 35 development centers and 15 distribution platforms, and employs 82,800 people in 30 countries worldwide. Valeo is listed on the Paris stock exchange and is a member of the CAC 40 index. The mission of the Powertrain Systems Business Group is to develop innovative powertrain solutions aimed at reducing fuel consumption and co2 emissions, without compromising on the pleasure and dynamics of driving. These innovations cover a complete product range, from the optimization of internal combustion engines to the varying degrees of electrification of vehicles, from stop-start systems to the electric car. Equal opportunities (gender, disabilities, mature workers, nationality, etc.) are at the heart of Valeo's recruitment policy.
Job Description
As BG Advanced Product Marketing Manager, your main responsibilities are to:
Deliver segmentation analysis and business plan for each individual advanced innovation developed by BG R&D
Identify powertrain technology trends, market drivers and highlights in each region.
Value Drivers
o Understand how the BG offering creates value for our OEM customers and end consumers, missing bricks and potential new tech.
o Propose & follow deep dives for emerging technologies.
Market Assessment
o Establish all the market data related to the BG innovations.
o Identify opportunities, design new business models and articulate value proposition for targeted markets.
Competitive Positioning
o Identify for new technologies key competitors and newcomers.
o Propose value propositions that differentiate our offerings from those of our competitors.
Customer and consumer Functional Needs
o Provide segmentation tools that enable identification of the most attractive offer for a given customer.
o Articulate OEMs' Marketing and end consumers' requirements early in the product development process
o Define the most profitable business model to address each targeted segment.
o Tease innovation at early stage
o Build potential scenario of OEMs' innovation introduction process
Marketing tools and Methodology
Comprehensive price positioning for BG innovations: systematic Innovation Pricing Process
Contribute to BG communication
o Support communication team for the organization of tech days, ride and drives and auto shows.
Team Management
Education & training
Engineering background & business school degree (MBA if possible) combined with a first experience in product marketing with wide experience of the automotive field.
Areas of experience
2-5 years in the automotive field (with OEM or supplier)
HR contact
Cleopatre SPIROPOULOS
Equal opportunities (gender, disabilities, mature workers, nationality, etc.) is at the heart of Valeo's recruitment policy.
Offres d'emploi
Ils ont travaillé ici
Imen AOUIDA
Mohamed Swelam
Embedded Software Engineer
Pauline ROUANET
Etudiante en logistique


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Catalog Item
$ 5,100.00 $ 3,950.00
Discount from MSRP
Item No. 1188768
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For further information or assistance on this item, call 203-847-1596 ext. 2206.
This French Provincial "Comtoise" Clock, C.1875, Features An Embossed Brass Front & Pendulum, An Enamel Face And Two Solid Iron Weights. The Pine Case Is Painted, However This Is Not The Original Paint Used On This Piece.
10 D x 92 H x 22 L


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Madic takes Mat to Larin when he wants to see Elayne and Nynaeve. She disappears out of sight when they confront Teslyn and Joline. She reappears, however, to summon Mat to Tylin. He is glad that she comes to save him from the Aes Sedai, but Laren assures him that the Queen really wants to see him.
When the strange relationship between Mat and the Queen starts, Larin personally brings Mat a basket sent by Tylin for breakfast as she did with supper the night before.