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5.	When you get drunk, you can tell everyone that you are just researching the law of diminishing marginal utility.
4.	You can talk about money without having to make any. 3.	You can say “trickle down” with a straight face.
2.	When you are in the unemployment line, at least you know why you are there. 1.	If you rearrange the letters in ECONOMICS, you get COMIC NOSE.
The interrelationship between AS and AD is captured in the circular flow diagram. AS (production by firms) creates output and income, and hence AD (the potential demand to buy that output.
The AS/AD model separates long-run aggregate supply from short-run aggregate demand forces. Demand-side policies (monetary and fiscal policy) shift the AD curve. Supply-side policies work by increasing potential output.
Politicians are not constrained by models. They can, and do, often emphasize different interconnections.
Six assumptions of the AS/AD model lead to problems with fiscal policy: Financing the deficit has no offsetting effects. The government knows what the situation is. The government knows potential income. The government has flexibility in changing spending and taxes. The size of the government debt doesn’t matter. Fiscal policy doesn’t negatively affect other goals.
Some economists believe that government financing of deficit spending offsets the deficit’s expansionary effect. They believe that government borrowing increases interest rates and crowds out private investment.
Crowding out – the offsetting of a change in government expenditures by a change in private expenditures in the opposite direction.
Some economists argue that the effect of government expenditures is negative. They consider private spending to be more productive than government spending.
Crowding out also works in reverse in contractionary fiscal policy. When the government runs a surplus, it buys back bonds. Interest rates will drop, stimulating investment.
Data problems limit the use of fiscal policy for fine tuning. Getting reliable numbers on the economy takes time. We may be in the middle of a recession and not know it.
The government has large econometric models and leading indicators to predict where the economy will be in the near future. Economic forecasting is still very much an art and not a science.
No one knows for sure the level of potential income. Potential income has been called the full-employment level of income.
In most cases, the U.S. economy is in an ambiguous state. Some economists will call for expansionary policy and others call for contractionary policy.
Putting fiscal policy into place takes time and has serious implementation problems. Numerous political and institutional realities in the U.S. today make it a difficult task to implement fiscal policy.
Squabbles between Congress and the President may delay implementing appropriate fiscal policy for months, even years.
These is no inherent reason why the adoption of activists policies should have caused high government deficits year after year.
Activist policy has led to an increase in government debt because: Early activists favored large increases in government spending as well as favoring the government's using fiscal policy. Politically, it is much easier for government to increase spending and decrease taxes than vice versa.
If one believes that debt is harmful, then there might be a reason not to conduct expansionary fiscal policy, even when the model calls for it.
An economy has many goals – achieving potential income is only one of those goals National economic goals often conflict.
While the six problems listed above do not necessarily eliminate fiscal policy altogether, they severely restrict it. Fiscal policy is a sledgehammer, not an instrument for fine-tuning.
Supply Side policies. Supply side policies aim to… Improve the efficiency of factor markets, to boost productivity and hence the overall capacity of the.
POLITICS, DEFICITS, AND DEBT Deficits. Laugher Curve When Albert Einstein died, he met three New Zealanders in the queue outside the pearly gates. To.
Fiscal Policy CHAPTER 32 C H A P T E R C H E C K L I S T When you have completed your study of this chapter, you will be able to 1 Describe the federal.
Ch. 14: Fiscal Policy Federal budget process and recent history of outlays, tax revenues, deficits, and debts Supply-Side Economics Controversies on effects.
Presentation on theme: "State College Community Land Trust Building Community Through Home Ownership."— Presentation transcript:
2 THE REALITIES OF THE MARKETPLACE Many low and modest income jobs are in town Families with low and modest incomes benefit from living near their work In-town real estate is expensive and getting more so each year Urban home ownership decreases as rental housing increases
5 WHAT IS A COMMUNITY LAND TRUST? Private, nonprofit, community-based organization Governed by board representative of community interests For example, our board consists of: – – One-third CLT homeowners – – One-third community representatives – – One-third public representatives 5
6 KEY OBJECTIVES OF COMMUNITY LAND TRUSTS Provide access to housing for people who are otherwise denied 6 Preserve neighborhood resources Empower residents through involvement and participation in the organization Preserve the affordability of housing permanently
7 Acquires properties through donation or purchase Separates ownership of the land from the home – – CLT retains ownership of the land – – Homeowner purchases and owns the home – – CLT leases land to homeowner under a 99- year lease 7 HOW DOES A CLT WORK?
8 STATE COLLEGE COMMUNITY LAND TRUST (SCCLT) Formed in 1996 at the request of State College Borough Focus is on buying, rehabilitating, and selling houses SC Borough provides HUD money to SCCLT for purchases 8 Member of the National Community Land Trust Network One of three CLTs in Pennsylvania
9 MISSION OF SCCLT The SCCLT supports vibrant neighborhoods by creating and maintaining sustainable housing opportunities for families and individuals who value living in the Borough of State College. 9
10 10 College Heights Highlands State College South Tusseyview Greentree Holmes-Foster SCCLT SINCE 1996 Over 30 households have become homeowners for the first time These homes are located throughout the Borough
12 HOW DOES THE SCCLT WORK? 12 SCCLT retains deed to the land Market and sell house (aka “improvements”) to an income-qualified buyer Lease the land to the homeowner at nominal fee Homeowner responsible for taxes and maintenance of house and land Homeowner and SCCLT share in equity upon resale
13 When possible, rehab uses environmentally friendly materials All replacement appliances are Energy Star™ models SCCLT GREEN INITIATIVE 13 Installation of low flow faucets, shower heads and toilets All houses receive an energy audit Actively seeking grants for energy efficient rehab
14 HOW DOES SCCLT KEEP THE HOME PERMANENTLY AFFORDABLE? Homeowner(s) agree to share with future homeowners the affordability that was created for them Seller is allowed to receive price reflective of the value invested in the property Selling price is limited to preserve affordability to the next buyer House is re-sold to a SCCLT qualified buyer SCCLT has first refusal to purchase the house back from the homeowner Benefits of home ownership are preserved for future generations 14
15 HOW DOES THE BOROUGH BENEFIT? Residential neighborhoods are preserved Older deteriorating homes are rehabilitated and given new life Young families move into the Borough Brings workers closer to their jobs and students closer to their schools 15
17 HOW DOES THE HOMEBUYER BENEFIT FROM SCCLT? Makes first-time home purchase affordable Advantages of an excellent support system – – Free legal assistance at closing – – Home has been rehabilitated – – SCCLT provides a free energy audit of the house – – Free financial counseling Social benefits – – Join a group of fellow homeowners – – Help others become first-time homeowners – – Participate in SCCLT social activities Practical benefits – – Freedom from rent – – Build equity for the future – – Personal pride in helping to sustain the community 17
18 HOW CAN YOU HELP? Sell or donate your house to the SCCLT Become a member Volunteer Donate Spread the word! 18
19 19 This presentation represents the collaborative efforts of many involved with the State College Community Land Trust. A sincere thank you to all those who had a hand in creating this presentation, among whom are: The Market/Outreach committee The Board of Directors and the Executive Director The Planning Office of the Borough of State College Research and script development.....Bob Leonard Graphic design.....John Hiester
1 Green Retrofit Program for Multifamily Housing HUDs Office of Affordable Housing Preservation (OAHP) IPED June, 2009.
1 The Development Process An Overview Forming the development concept Forming the development concept Evaluating your capacity and the needs of your community.
Delaware State Housing Authority FY 15 Joint Committee On Capital Improvement Public Hearing February 11, 2014 Delaware State Housing Authority 18 The.
American Planning Association 2007 National Planning Excellence Award for Innovation in Neighborhood Planning in honor of Jane Jacobs.
Virginia Housing Coalition 2013 Housing Credit Conference Deal Structuring, Fundamentals, and Financing and Legal Issues.
David Rodgers Executive Director CDS Co-operatives ICA Housing - President All Party Group on Co-operatives and Mutuals 9 May 2012 Northern Ireland Assembly,
tables.googlelabs.com “… focus is on fusing data management and collaboration: merging multiple data sources, discussion of the data, querying, visualization, and Web publishing.” “The power of data is truly harnessed when you combine data from multiple sources. Fusion Tables enables you to fuse multiple sets of data when they are about the same entities. In database speak, we call this a join on a primary key but the data originates from multiple independent sources.” Data Fusion | VLDB 2009 Tutorial | Luna Dong & Felix Naumann
Semantics of NULL “unknown” There is a value, but I do not know it. E.g.: Unknown date-of-birth “not applicable” There is no meaningful value. E.g.: Spouse for singles “withheld” There is a value, but we are not authorized to see it. E.g.: Private phone line Data Fusion | VLDB 2009 Tutorial | Luna Dong & Felix Naumann
What else is there? Consistent Query Answering Avoid conflicts and report only certain tuples Those that appear in every repair [FFM05] “Possible worlds” models Build all possible solutions, annotated with likelihood Yes/No/Maybe [DeM89] Probability value [LSS94] Probabilistic databases [SD05] Extend algebra to produce probabilities Extend query language to query and export probabilities Data Fusion | VLDB 2009 Tutorial | Luna Dong & Felix Naumann
52 Intuitions Data sources are of different quality and we trust data from accurate sources more Data Fusion | VLDB 2009 Tutorial | Luna Dong & Felix Naumann
53 Intuitions Data sources are of different quality and we trust data from accurate sources more Data Fusion | VLDB 2009 Tutorial | Luna Dong & Felix Naumann
55 Intuitions Data sources are of different quality and we trust data from accurate sources more The real world is dynamic and the true value often evolves over time E.g., person affiliation, business contact phone Data Fusion | VLDB 2009 Tutorial | Luna Dong & Felix Naumann
56 Intuitions Data sources are of different quality and we trust data from accurate sources more The real world is dynamic and the true value often evolves over time E.g., person affiliation, business contact phone Data sources can copy from each other and errors can be propagated quickly Data Fusion | VLDB 2009 Tutorial | Luna Dong & Felix Naumann
Consider accuracy of sources Consider freshness of sources Consider dependence between sources Data sources are of different quality and we trust data from accurate sources more The real world is dynamic and the true value often evolves over time E.g., person affiliation, business contact phone Data sources can copy from each other and errors can be propagated quickly Data Fusion | VLDB 2009 Tutorial | Luna Dong & Felix Naumann
Considering accuracy can often improve truth discovery S1 S2 S3 Stonebraker MIT Berkeley Dewitt MSR UWisc Bernstein Carey UCI AT&T BEA Halevy Google UW (American short-story Writer and Novelist, Nobel Prize for Literature in 1949, ) S1 is more accurate; trusting it more can help find the correct affiliation for Carey
Properties A value provided by more accurate sources has a higher probability to be true Assuming uniform accuracy, a value provided by more sources has a higher probability to be true Source accuracy Source trustworthy Value confidence Value probability Consider value similarity Continue until source accuracy converges
Fresh ness Cove rage Exact ness How many transitions are captured How many transitions are not mis-captured How quickly transitions are captured Mis-capturable Dewitt S Ѳ(2000) 2008 2003 2005 2007 UWisc MSR UW  Capturable Mis-captured Exactness = 1-#Mis-Captured/#Mis-Capturable (e.g., 1-2/5=.6) Captured Coverage = #Captured/#Capturable (e.g., ¼=.25) Freshness() = #(Captured w. length<=)/#Captured (e.g., F(0)=0, F(1)=0, F(2)=1/1=1…)
10 sources voting for an object Count =? How to compute vote count? Count =? 1 S4 .4 1 .7 3 S2 2 S5 S6 S3 S1 S7 S8 Count=? How to detect copying? S9 S10
Fresh ness Cove rage Exact ness Challenge 3: Source profiling Current effort: accuracy (coverage, exactness, freshness) Data properties can be different for different categories of data Source A is a vertical source on restaurants Source B knows very well about NYC Data properties can evolve over time Source C improves its data over time Directions: partition data into different portions and profile on each portion Data Fusion | VLDB 2009 Tutorial | Luna Dong & Felix Naumann
Challenge 9: Fuse data w. different schemas E.g., Contact information from three sources S1: (pid = “1”, work phone = “1234”, home phone = “8765”, mobile phone = “4321”) S2: (pid = “1”, daytime phone = “1234”, evening phone = “4321”) S3: (pid = “1”, phone = “4321”) Directions: Combine data fusion w. schema matching Data Fusion | VLDB 2009 Tutorial | Luna Dong & Felix Naumann
B: are different businesses sharing the same phone# C: are different businesses, only one with correct phone# 102 Data Fusion | VLDB 2009 Tutorial | Luna Dong & Felix Naumann
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2. MPF and the discovery of CDKs 3. CDK regulation of mitotic entry and exit 4. Regulation of G1-S 5. DNA replication control 6. Cell cycle checkpoints 7. Discussion of papers
2. Logic of cell cycle circuitry and switches 3. Experimental approaches Many topics we have no time to cover, or will cover in little detail: chromosome dynamics, cytokinesis, centriole replication, cancer cell cycles, developmental/alternative cell cycles, checkpoints, DNA replication mechanisms, meiotic cell cycle, growth control
1830’s Schleiden & Schwann organisms are made of cells 1850’s Schultze cytosol (protoplasm) and nucleus defined as separate entities in animal and plant cells 1850’s Remak and Virchow omnis cellula e cellula --all cells come from other cells 1880’s Fleming and Strasburger mitosis (chromosomes look like threads) 1950’s Stages of cell cycle are defined DNA replication as a discrete event (S phase) 1960’s Continuous and discontinuous events RNA synthesis, protein synthesis, cell growth--continuous DNA synthesis, Mitosis--discontinuous
G1 S G2 Mitosis Interphase 1 2 G1 M G2 S Relative Amount time Protein RNA DNA Mass/Size Restriction Point S phase and Mitosis are defined by processes G1 and G2 (gap phases) are defined by timing G1 (and G2?) can be split into more meaningful sub-stages by molecular and physiological criteria: Restriction Point in mammalian tissue culture cells defined by serum sensitivity
Mitosis is subdivided into different stages Mitosis involves the formation of a mitotic spindle with all the chromosomes properly aligned (A-D), followed by mitotic exit where sister chromosomes are separated, a cleavage furrow forms, nuclear envelope re-forms, and chromosomes decondense.
The cell cycle can be broken into subcycles whose relationships change in different cell types and under different circumstances Timing in a typical somatic cell: 1. DNA replication S phase 2. Centrosome duplication (microtubule organizing center) S phase 3. Nuclear Division (karyokinesis) Mitosis 4. Cell Division (cytokinesis) Mitosis 5. Cell Growth Throughout In a typical somatic cell 1-5 are all regulated and coupled
Cell Cycle States are Regulated: nucleocytoplasmic ratio controls replication II. (Sudbery and Grant, 1976) Physarum (slime mold) Starved plasmodium no growth, no DNA replication UV irradiate ~50% of nuclei inactivated Remaining nuclei replicate and divide until nucleo-cytoplasmic ratio is restored
Properties of Xenopus system: Cell free extracts can cycle between S phase and Mitosis Extracts can be manipulated to effect a mitotic arrest: chelate calcium > stabilize cytostatic factor (CSF) Feedback controls/checkpoints are missing* -extracts can cycle without nuclei G1 regulation is absent Most components needed to drive cell cycle are already present in the cytoplasm to support rapid embryonic cell cycles No transcription necessary. Only a single protein needs to be translated to drive the cell cycle forward. If enough nuclei are added then feedback regulation and G1 intervals appear.
Serial injections can be repeated indefinitely until original source of MPF is diluted away Yoshio Masui and co-workers MPF activity fluctuates and is present in both oocytes and fertilized embryos Tim Hunt and co-workers Cyclin synthesis and abrubt degradation mirrors rise and fall of MPF activity
Lohka and Maller Stabilize MPF in vitro from Xenopus extracts and fractionate: MPF has two components 32 kd and 45 kd; MPF posseses kinase activity 45 kd protein = cyclin B Kinase activity only present when both subunits are present Several groups: Murray and Kirschner Take cell free extract and RNase treat to destroy all endogenous mRNAs Inactivate RNase with inhibitor and add no RNA or cyclin mRNA activate extract to induce interphase and add sperm nuclei Part I MPF appears to have a kinase activity--is this rigorous proof? Could it be other proteins in the prep? Histone H1 is a good in vitro substrate for CDKs, often used to assay CDK activity
Murray and Kirschner ∆13 equiv. to wt cyclin B ∆90=nondegradable cyclin missing destruction box Cyclin synthesis drives activation of MPF Cyclin destruction is required to inactivate MPF and drive cells into interphase MPF is required for cyclin destruction Oscillator behavior of cell cycle is explained: cyclin MPF Part I--what does panel b show, what about panel c? PartII-what is paradoxical about this result? Part III-In lower panel the cells enter anaphase but the chromosomes remain condensed, suggesting high mitotic activity. What does this suggest about regulation of anaphase? Cyclin destruction is NOT required to initiate anaphase
Hartwell and colleagues, Nurse and colleagues budding yeast	fission yeast G1-S blocked cdc mutant Why did Hartwell and Nurse look for temperature sensitive mutants? Would you expect most ts lethal mutants to have a cdc block? cdc28 (budding yeast) has two arrest points pre-S phase, and pre-M cdc2 (fission yeast) shows arrest at G2/M, but also has dominant alleles that give a wee phenotype phenotypes suggest that these two cdcs have a critical role in cell cycle regulation mitotic cdc mutant
budding yeast CDC28 = fission yeast cdc2 = Xenopus MPF 32kd subunit aka CDK1 budding yeast daf1/whi1 = a cyclin (later renamed Cln3) fission yeast cdc13 = a B-type cyclin homolog Key enzyme for cell cycle regulation is now defined as a cyclin dependent kinase complex (CDK) composed of a catalytic kinase subunit and a cyclin that activates the kinase Since then things got more complicated: Multiple CDKs, Multiple cyclins and Interacting proteins discovered All eukaryotes use the same set of proteins for cell cycle regulation with some species specific variation 2001 Nobel Prize in Physiology or Medicine given to Tim Hunt, Lee Hartwell, and Paul Nurse for their pioneering work in cell cycle regulation
Somatic cells and yeasts have a G1 period with low CDK activity Somatic cells and yeasts have multiple cyclins or CDKs that control progression through G1, S phase and mitosis Somatic cells and yeasts have feedback controls that gate each transition to ensure proper completion of previous events
Activation by cyclin binding Activation by phosphorylation (CAK) Activation by dephosphorylation (CDC25, Cdi1) Activation by destruction of inhibitor (Skp1-Cullin-F box complex aka SCF) Inactivation by cyclin destruction (Anaphase Promoting Complex/Cyclosome aka APC/C) Inactivation by phosphorylation (Wee1) Inactivation by inhibitory binding proteins (KIP/CIP/WAF/KRP and INK) Substrate specificity (CDK-cyclin combinations) Subcellular localization CDK abundance usually not regulated
CDK Thr160 +cyclin T loop flattened. Phospho T160 forms stabilizing interactions that optimize binding site With substrate peptide SPXK-containing peptide fits into pocket and interacts with T loop, including Phospho T160.
inactive active We won’t talk about much about mitotic CDK substrates, but they are obviously very important. What criteria would you use to establish that a protein is a substrate for a mitotic CDK? -phosphorylated in mitosis -can be phosphorylated by highly purified or recombinant mitotic CDK in vitro on same sites as in vivo -Loss of in vivo phosphorylation when kinase is inhibited or knocked down Very hard to prove conclusively Loop leads to explosive auto-activation of CDK once its activity rises above a certain threshold What are the substrates CDK1-cyclin B that lead to mitotic entry and progression? Cdc25, Histone H1, lamins, cyclin B and many more
APC/C is a E3 specificity factor for ubiquitin ligase pathway examples: B cyclin Cdc20 Cdc20 + + or Pds1 or Cin8 Hct1 activator and specificity factor RXXL destruction (D) box- containing substrates Cdc20, Hct1 (Cdh1) KEN-box substrates Hct1 only core complex KEN RXXL How would you show that a destruction box is necessary and sufficient to target a protein for degradation? -delete and stabilize protein -move to heterologous protein and confer mitotic instability Cdc20 was isolated as a cdc mutant. What is its arrest phenotype? Targeting by APC/C leads to rapid degradation by the 20S proteasome
B Cyclins and Pds1(Securin) are key substrates of APC/C: Nondegradable cyclin blocks MPF destruction but does not block anaphase APC/C has at least one more target whose destruction promotes anaphase Pds1/Securin destruction releases a protease, separase, that degrades cohesisns and allows sister chromatids to separate
Decreased CDK activity and Separase release activate FEAR (Cdc14 early anaphased release) Cdc14 is a protein phosphatase that plays a central role in exiting mitosis Cdc14 dephosphorylates and activates cdh1 subunit of APC and Sic1 (a CDK inhibitory protein) to establish a stable G1 state with low CDK activity Cdc14 activates a second pathway called MEN (mitotic exit network) that initiates cytokinesis
CDK1-Cyclin B activates APC-Cdc20 directly or indirectly through phosphorylation A time lag between APC-Cdc20 activity and other essential mitotic events is essential Decreased CDK activity allows activation of Cdc14 mitotic exit pathway, Cdh1/Hct1 and establishment of a stable G1 state Regulation of APC/C by CDK1-Cyclin B generates a negative feedback to drive mitotic exit
32 G1 and G1-S regulation G1 is characterized by low CDK activity and high APC-Cdh1 activity What triggers initiation of S phase and cell cycle re-entry?
33 G1 and G1-S regulation I G1 is a major control point for most cell types: Growth factors present and extracellular conditions favorable: S phase M G1 Differentiation factors present, unfavorable conditions: G0 (temporary or permanent withdrawal from cell cycle) What triggers entry to S phase, what mechanisms prevent it? Cells must be growing and have reached a minimum size mammalian cells must not contact neighbors (contact inhibition) APC-Cdh1 must be inactivated to allow S phase cyclin accumulation CDK inhibitory proteins must be destroyed or titrated away In budding yeast and animal cells G1 CDK activity must reach a threshold value to trigger S phase
Restriction point in animal cells occurs late in G1 Serum withdrawal before R point--cells arrest in G1 Serum withdrawal after R point-cells complete S, G2 and M Restriction point G1 S Pardee (1974) Serum Dependent Independent Budding yeast cells have a G1 control point termed Start Remove nutrients prior to Start--G1 arrest Remove nutrients after Start--cells complete S, G2 and M Start
animal cells Growth factors in serum e.g. FGF,PDGF activation of RTK signaling transcription of D cyclins budding yeast nutrients (glucose, nitrogen etc.) increased protein translation rate Increased translation of Cln3 Similarities of Cln3 and D cyclins: messages and proteins are low abundance proteins are highly unstable length of G1 highly sensitive to dosage and expression levels control rate limiting step in G1-S transition neither are essential!
G1 cyclins Cln1, Cln2, Cln3 Sic1--CDK inhibitor--disrupts CDK active site, prevents ATP binding Transcription factors SBF, MBF--activators of Cln1, Cln2 and other S phase genes Whi5--negative regulator of SBF, MBF SCF--Skp1-Cullin-Fbox--E3 ubiquitin ligase targets G1 substrates (Elledge and Harper 1996) substrate Cullin F-box protein (adaptor) Skp1 Cdc4 is F box adaptor for Sic1 F-box proteins are specificity factors in SCF, often require phosphorylation for binding target In early G1: Sic1 and APC-Hct1/Cdh1 are dephos. and active. CDK activity is low
Cln3-Cdc28 As Cln3-Cdc28 activity builds: SBF/MBF become active Whi5 is phosphorylated and dissociates from SBF/MBF Cln1/2 and Clb5/6 are made SBF/MBF are further activated in a positive feed back loop Sic1 and Hct1 are inactivated in a negative feedback loop Whi5 SBF or MBF Cln1 Cln2 ? Clb5 Clb6 Cln1/2-Cdc28 What would the phenotype be of a whi5 mutant? a cdc4 mutant? a Cln3 mutant? SCF-Cdc4 Sic1 Clb5/6-Cdc28 Hct1/Cdh1
Tyers and colleagues Cdc4 binding of Sic1 depends on 6+ phosphorylations Triple mutant ∆cln1 cln2 cln3 is inviable ∆cln1 cln2 cln3 sic1 mutant--viability is rescued! Sic1 is key target of G1 cyclins Sic1 becomes multiply phosphorylated by CDKs during G1 followed by abrupt degradation Replacement with a high affinity Cdc4 binding site causes premature S phase initiation and genome instability Cooperative phosphorylation ensures that a very high CDK activity must be present in order to degrade Sic1, and that Sic1 is degraded abruptly.
Can’t easily make cdc mutants with diploid mammalian cells Strategies for genetic analysis: dominant negatives overexpression (transfection) knockouts in ES cells, whole mice, or cell lines from KO mice siRNA-mediated knockdowns Why might a dn allele of CDK2 cause cell cycle arrest, yet the null mutation has almost no phenotype? Are knockouts always a better way to determine gene function? -redundancy -inappropriate substitution of related proteins Harlow and colleagues Dominant negative CDK mutations For many years CDK2/CycE thought to be a linchpin of G1-S regulation However, CDK2 and CycE KO cells have only mild S phase entry defects!
Unregulated cell division leads to defects in tissue morphogenesis, development and cancer Several G1 regulators are tumor suppressors or oncogenes-RB, INKs, D cyclins, CDK4 Two classes of negative regulators: CDK inhibitors INK4 (CDKN2) family specific for CDK4/6-Cyclin D complexes p21, p27,p57 proteins inhibit all CDKs RB-related proteins RB, p107, p130--bind to E2F complexes and repress S phase transcription Regulators show some functional overlap and tissue specificity e.g. RB is expressed in cycling cells, p107/p130 in quiescent cells, p27 is constitutively expressed,p21 is induced by checkpoint activation, p57 is expressed in neuronal cells, p16INK4b induced by negative growth factor TGF beta
cyclin Conformation change in CDK blocks cyclin binding CDK cyclin Kip Binds CDK-cyclin, blocks ATP binding and substrate access Early G1--INKs keep CDK4/6 cyclin D inactive, p27 keeps CycE-CDK2 inactive As CycD accumulates it overcomes INK binding to CDK4/6 CycD-CDK4/6 complexes compete p27 from CycE-CDK2 promoting S phase
E2F-DP RB CycE CycA S phase genes E2F-DP RB P Restriction point/late G1/S RB hyperphosphorylated by CDK2-CyclinE complexes dissociation from E2F-DP E2F-DP RB P Mid G1 RB partially phosphorylated by CDK4/6-D cyclins (priming) Early G1 RB hypophosphorylated E2F-DP RB P What is predicted phenotype of a RB phosphorylation site mutant? RB is phosphorylated by at least two kinase complexes. How would you figure out their relative contributions and whether the phosphorylations needed to be sequential? Loss of one copy of RB leads to tumors Animal DNA tumor viruses produce proteins (e.g. SV40 T antigen) that inactivate RB Plant DNA viruses have evolved the same trick CycD and CycE overexpressed in many cancers
Previous work on bulk synchronized cells indicates correlation between RB phosphorylation, Cyclin E transcription and Restriction Point Zetterberg and colleagues Time lapse videomicroscopy on single cells + immunofluorescence to look at timing of RB phosphorylation vs. R vs. S phase How do you produce synchronous cells? Yeast-pheromomone arrest, elutriation, cdc temperature arrest, HU (S phase) Animal cells-mitotic shakeoff, double thymidine block, colchicine arrest at mitosis How do you measure S phase? FACS, BrdU incorporation What is the molecular correlate of the Restriction point?
yeasts show evidence of size control nutritional shift experiment: move cells from rapid growth to slow growth conditions- observe a G1 (budding yeast) or G2 (fission yeast ) delay until a minmal size is reached How could one show a that a size checkpoint exists for mammalian cells? sort G1 cells into different size classes and measure G1 duration prolong prior cell cycle so that larger daughters are produced, look for shortened G1 Follow single cells by video microscopy, look for correlation between size and S phase Data on animal cells is controversial but evidence for G1 size control exists. Growth may also be cell cycle regulated: RB controls rRNA synthesis Tumors often have aberrant growth characteristics faster cell cycle, faster growth
Properties of DNA replication in eukaryotes: Occurs at a specific phase of the cell cycle--S Initiates from specific locations termed origins--well defined in budding yeast poorly defined in other organisms Occurs once and only once per S phase Completion of S phase is ensured by checkpoints S phase is regulated by oscillating CDK activity Low CDK activity required to prime origins High CDK activity required to fire origins and block re-priming
Cdc6 and Cdt1-- origin priming proteins-activity is tightly regulated Orc--origin recognition complex--binds origins throughout cell cycle, required for origin firing Mcms--(mini-chromosome maintenance)-part of a hexameric origin unwinding complex required for initiation, AAA ATPase family Cdc7-Dbf4--kinase complex analogous to CDK-cyclin required for origin firing Geminin (metazoans only) inhibits Cdt1 mediated MCM loading at origins S phase CDKs--Clb 5/6-Cdc28 in budding yeast, CycE-Cdk2, CycA-Cdk2 in mammals
Origin “Licensing” Blow, Laskey and coworkers Naked DNA + interphase Xenopus extract Chromatin assembly, NE assembly, 1 round of DNA replication Mitosis Next round of DNA replication Add replicated G2 nuclei to fresh interphase extract control No replication Next round of DNA replication +NE permeabilizing detergent lysolecithin Something present in early interphase extracts that allows replication: licensing factor Licensing factor cannot cross NE. Lf gets made in early interphase, destroyed during S remade during M
(A) licensing factor (+) generated during M-G1 transition (B) + binds to chromatin prior to NE assembly (C) further access to + restricted by NE (D) nuclear + destroyed (-) upon S phase initiation (E) cytoplasmic + decays during late S and G2 Details vary between organisms Principles of model proved correct: Highly regulated and labile factors are generated in G1 that bind to origins (Cdc6, Cdt1) Cdc6 and Cdt1 allow loading of MCM complex prior to S phase S phase CDK activity simultaneously fires loaded origins and inactivates or destroys Cdc6, Cdt1, MCMs Multiple redundant mechanisms are involved
Crystal structure of archeal MCM complex Blue indicates + charge region that could accommodate ss or ds DNA
Cdc6, Cdt1 and MCM complex can only load onto origins in G1 After S phase CDK activation: Geminin (A APC-Cdh1 substrate) is stabilized and inhibits MCM loading origin unwinding by MCM triggers SCF-Skp2 mediated degradation of Cdt1 phosphorylation of priming proteins blocks activity, nuclear entry or origin binding
Checkpoint: mechanism to ensure that the next cell cycle stage is not entered until the events of the current stage are completed Examples of important checkpoints: Spindle assembly--ensures all chromosomes attached to spindle prior to anaphase S-phase completion--ensures that replication is complete prior to mitotic entry DNA damage-blocks S phase initiation in G1 cells, blocks G2-M in S phase cells until DNA damage repaired
Isolate mutants that are hypersensitive to DNA damaging agents Rescreen for those that don’t arrest cell cycle properly How could you isolate spindle assembly checkpoint mutants?
Sensors-- Mre11 complex? Most of these proteins are conserved signal transducers p53 is a metazoan protein that helps decide whether a damaged cell arrests or commits suicide Targets
Announcements Monday, April 16: the cell cycle, pp Wednesday, April 18: protein synthesis, pp Friday, April 20: protein targeting,
P53, Apoptosis, Cancer, More Regulation G1 checkpoint Controlled by G1 Cdk-cyclin G1 cyclin levels also vary with the cell cycle Many additional levels.
G2/M: Chromosome condensation SMC family of proteins structural maintenance of chromosomes large coiled coil proteins with ATPase domain interact in complexes.
Introduction The timing and rates of cell division in different parts of an animal or plant are crucial for normal growth, development, and maintenance.
New Energy Horizons Opportunities and Challenges Fault Current Contributions from Wind Plants Dean Miller PacifiCorp July 25, ppt download
New Energy Horizons Opportunities and Challenges Fault Current Contributions from Wind Plants Dean Miller PacifiCorp July 25, 2012 1.
1 New Energy Horizons Opportunities and Challenges Fault Current Contributions from Wind Plants Dean Miller PacifiCorp July 25, 2012 1
4 New Energy Horizons Opportunities and Challenges Working Group Assignment Prepare a Report: To characterize and quantify short circuit current contributions to faults from wind plants for the purposes of protective relaying and equipment rating, and to develop modeling and calculation guidelines for the same. Started 2008 Draft 7.1 of the Report Was Distributed Estimated Completion Date: 2013
5 New Energy Horizons Opportunities and Challenges The Issue  Wind Plants use different types of generators than other power generation facilities  Wind turbine generators tolerate rapid fluctuations in prime mover, due to wind speed fluctuations  Traditional rigid mechanical and electrical coupling of a turbine and synchronous generators will not tolerate the rapid fluctuation in the prime mover  Response to faults is different  Safe, reliable operation of the electrical power system requires the ability to predict and model the sources of fault current
7 New Energy Horizons Opportunities and Challenges Wind Plant Configuration Multiple wind turbine generators ranging in size (500 – 7,000 kVA) Each wind turbine generator with its own step-up transformer stepping the voltage from 600 – 1000 V up to typically 34.5 kV Collector lines, mostly under ground, bring the output of several generators back to a collector substation At the collector substation there are breakers for the individual collector lines and the power is transformed from the 34.5 kV to the Transmission Provider’s system voltage
8 New Energy Horizons Opportunities and Challenges Wind Plant Configuration (cont.) Reactive power devices may also exist in the collector substation Tie transmission line to the Point of Interconnection (POI) substation POI substation ties the Wind Plant into the power network
12 New Energy Horizons Opportunities and Challenges Type 1 WTG Response to Fault Single Phase to Ground fault on the Terminal of the Generator Step- up Transformer Study results have refined some of the earlier assumed theories.
14 New Energy Horizons Opportunities and Challenges Type 2 WTG Response to Fault Three Phase Fault on the Terminal of the Generator with Different Levels of External Rotor Resistance Model was validated with data from a wind plant fault event.
16 New Energy Horizons Opportunities and Challenges Type 3 WTG Response to Fault Fault current for a fault reducing the voltage at the unit step-up transformer MV terminals to 20%. Initially with crowbar action
17 New Energy Horizons Opportunities and Challenges Type 4 Wind Turbine Generator Synchronous or induction generator Varies firing angle of inverters for real & reactive power control Fault current is limited and maintained by the by power electronics
18 New Energy Horizons Opportunities and Challenges Type 4 WTG Response to Fault Single Phase to Ground Fault on the Terminals of the Generator
19 New Energy Horizons Opportunities and Challenges Type 5 Wind Turbine Generator Synchronous generator Variations in wind turbine speed are compensated in the hydraulic transmission Reactive power controlled by field current Fault current similar to any other synchronous generator
20 New Energy Horizons Opportunities and Challenges Protective Relaying for the Collector Substation Collector lines Combination of directional and non-directional overcurrent relays Coordinated with generator step-up transformer fuses and relays on the other lines 20
21 New Energy Horizons Opportunities and Challenges Protective Relaying for the Collector Substation (continued) Power Transformer Current differential & sudden pressure relays to detect internal faults Overcurrent relays to protect the transformer from damage due to slow clearing of line or bus faults 34.5 kV bus High speed protection is desirable to limit damage Including the bus in the transformer protection zone may delay the restoration of the bus 21
23 New Energy Horizons Opportunities and Challenges Tie Line Protective Relaying POI adjacent to the Collector Sub Common ground mat Bus differential relaying POI remote from the Collector Sub Line current differential relaying system Works well for variable sources of fault current Optical fiber cable installed on the transmission line provides the communication medium 23
24 New Energy Horizons Opportunities and Challenges Over/under Voltage Magnitude & Frequency Installed at the POI Sub For the protection of the Transmission Provider’s equipment and customer’s equipment Multiple pickup levels with different time delays Pickup levels closest to the normal operation range have the longest time delays Disconnect the 34.5 kV collector lines 24
25 New Energy Horizons Opportunities and Challenges Fault Interrupting Equipment Issues Additional fault current from the wind plant Additional fault current due to the enhancements of the transmission network to handle the additional load current Higher X/R ratios increases the DC component Characteristic of fault current from some types of WTG delay the first zero crossing 25
26 New Energy Horizons Opportunities and Challenges Analysis of Data from Fault Events Analysis of data from relays for tie line faults 4 fault events, 2 with type 2 WTG, 2 with type 3 3 with Single phase to ground faults, 1 with phase to phase Direct calculation of wind plant collective negative and zero sequence impedance Use of fault study program to determine generator positive and negative sequence impedance 26
27 New Energy Horizons Opportunities and Challenges Example of Data from Fault Event 11 – 1.5 MW type III wind turbine generators Collector substation with a 34.5 to 115 kV wye-delta- wye step up transformer 17.7 MW and 3.2 MVAR into the transmission system prior to the fault A phase to ground fault occurred on the line to the network substation, 3.8 km from the network substation. 27
32 New Energy Horizons Opportunities and Challenges Conclusion Draft 7.1 of the report has been distributed to the working group members All of the writing assignment have been completed 90 page report 16 authors Editorial and technical committee approval process will most likely to take most of 2013. 32
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1 Distributed Generation and Power Quality. 2 Distributed Generation Distributed generation (DG) or distributed generation resources (DR) –Backup generation.
Learning Curve. Performance improvement As an organization gains experience in manufacturing a product, the labor inputs required per unit of output diminish. - ppt download
Learning Curve. Performance improvement As an organization gains experience in manufacturing a product, the labor inputs required per unit of output diminish.
Presentation on theme: "Learning Curve. Performance improvement As an organization gains experience in manufacturing a product, the labor inputs required per unit of output diminish."— Presentation transcript:
2 Performance improvement As an organization gains experience in manufacturing a product, the labor inputs required per unit of output diminish over the life of the product As an organization gains experience in manufacturing a product, the labor inputs required per unit of output diminish over the life of the product If you repeat a new task continually your performance improves. Performance time drops off dramatically at first, and it continues to fall at some slower rate until a performance "plateau, a leveling off" is reached If you repeat a new task continually your performance improves. Performance time drops off dramatically at first, and it continues to fall at some slower rate until a performance "plateau, a leveling off" is reached Learning phenomenon occurs for groups and organizations as well as for individuals Learning phenomenon occurs for groups and organizations as well as for individuals
3 Learning curve General form of the pattern is called the learning curve General form of the pattern is called the learning curve
4 General equation for the learning curve Y X = kX L Y X = kX L –Y X = labor hours required to produce Xth cumulative unit of output –k = labor hours required to produce first unit of output (initial productivity) –L = index of learning –X = production unit number
7 Learning rate (or rate of learning) Learning rate is specified as a percentage Learning rate is specified as a percentage i.e. 80% curve - each time cumulative output doubles the newest unit of output requires 80% of the labor of the reference unit Also interested in average labor per unit for certain quantity production run (from above, average labor per unit assuming 4 units is 78.55 hours) Also interested in average labor per unit for certain quantity production run (from above, average labor per unit assuming 4 units is 78.55 hours) UnitHours 1100 280 (3)(70.21) 464
8 Determining index of learning from the learning rate Previously, L = (y2 - y1)/(x2 - x1) = (log Y X2 - log Y X1 )/(log X2 - log X1) Previously, L = (y2 - y1)/(x2 - x1) = (log Y X2 - log Y X1 )/(log X2 - log X1) L = (log (Y X2 /Y X1 ))/(log (X2/X1)) L = (log (Y X2 /Y X1 ))/(log (X2/X1)) For first unit, X1 = 1 and Y X1 = k For first unit, X1 = 1 and Y X1 = k –L = (log (Y X2 /k))/(log (X2)) –i.e. for learning rate of 80%, L = (log (80/100))/(log (2)) = -0.3219
9 Rate of learning to use Rate of learning is not the same in all manufacturing applications - learning occurs at a higher rate in some applications than others and is reflected by more rapid descent of the curve Rate of learning is not the same in all manufacturing applications - learning occurs at a higher rate in some applications than others and is reflected by more rapid descent of the curve The rate is influenced by The rate is influenced by –Worker experience level –Desired degree of conservatism applied Amount of process controlled by machine should be taken out of the labor content when applying the effect of learning and then added back in with no adjustment for learning Amount of process controlled by machine should be taken out of the labor content when applying the effect of learning and then added back in with no adjustment for learning The approach assumes learning continues indefinitely - is this realistic? The approach assumes learning continues indefinitely - is this realistic?
10 Example Captain Nemo, owner of the Suboptimum Underwater Boat Company (SUB) is puzzled. He has a contract for 11 boats and has completed 4 of them. He has observed that his production manager, young Mr. Overdoit, has been assigning more and more people to torpedo assembly after the construction of the first four boats. The first boat, for example, required 225 workers, each working a 40-hour week, while 45 fewer workers were required for the second boat. Mr. Overdoit has told them that "this is just the beginning" and that he will complete the last boat in the current contract with only 100 workers! Captain Nemo, owner of the Suboptimum Underwater Boat Company (SUB) is puzzled. He has a contract for 11 boats and has completed 4 of them. He has observed that his production manager, young Mr. Overdoit, has been assigning more and more people to torpedo assembly after the construction of the first four boats. The first boat, for example, required 225 workers, each working a 40-hour week, while 45 fewer workers were required for the second boat. Mr. Overdoit has told them that "this is just the beginning" and that he will complete the last boat in the current contract with only 100 workers! Mr. Overdoit is banking on the learning curve, but has he gone overboard?
11 Example SUB has produced the first unit of a new line of minisubs at a cost of $500,000 - $200,000 for materials and $300,000 for labor. It has agreed to accept a 10 percent profit, based on cost, and it is willing to contract on the basis of a 70 percent learning curve. What will be the contract price for three minisubs? SUB has produced the first unit of a new line of minisubs at a cost of $500,000 - $200,000 for materials and $300,000 for labor. It has agreed to accept a 10 percent profit, based on cost, and it is willing to contract on the basis of a 70 percent learning curve. What will be the contract price for three minisubs?
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