As republicans take over the senate, they have lost some of their most willing allies on the democratic side

Last night saw the Republican Party retake the Senate, and win their largest majority in the House for more than 60 years. Michele Swers reflects on the results, writing that despite concentrating on state-level issues, many Democrats were dragged down by President Obama’s unpopularity and the national climate. She writes that while the Republican Party may be celebrating their victory today, they have kicked out many of the Democrats that would have been their allies on key issues such as trade and tax reform, meaning that legislative compromises are now even less likely

The nuclear option will increase polarization in the Senate and shift power to the executive branch

The so-called “nuclear option” to limit the filibuster was talked about for years before Senate Majority Leader Harry Reid finally moved forward with it last week. Michele Swers describes this move as the culmination of years of increasing polarization in the Senate. She goes on to argue that the elimination of the filibuster will only make bipartisan deals more difficult to attain and will ultimately shift power away from the legislative branch and into the executive

Partisan politics over the government debt ceiling has put the US on the verge of economic disaster

With no agreement yet reached by Congress over raising the US government’s borrowing limit, the country will effectively run out of money to pay its debts on October 18th. Michele Swers gives an overview of the lead-up in Congress to the current impasse over the debt ceiling, and how partisans are grasping at procedural tools such as reconciliation, invoking the 14th amendment, or even minting a $1 trillion coin to overcome the deadlock

Cracks in Republican unity between Trump and Congress are already beginning to show

Donald Trump will enter the White House this Friday facing a Republican-controlled House and Senate. Michele L. Swers looks ahead to what we might expect from President Trump and the 115th Congress, writing that while they may initially seek areas of common ground, clashes on issues like the repeal and replacement of Obamacare, foreign policy, and infrastructure spending may mean a rocky relationship lays ahead

Paul Ryan's retirement means the season for legislating is now officially over

This week, the Speaker of the House, Paul Ryan (R-WI), announced that he would be handing in his gavel at year's end and would not run for reelection. Michele L. Swers writes that before becoming Speaker, Ryan was a well-respected conservative in pursuit of budgetary reform. In a job that he only took reluctantly, his ability to legislate effectively as Speaker has been stymied not only by divisions within Congressional Republicans, but by a President whose agenda has departed greatly from Ryan’s own vision of conservative leadership

Isolation and engineering of a high affinity antibody against P-selectin glycoprotein ligand-1 (PSGL-1)

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2005.Vita.Includes bibliographical references (leaves 87-91).We aim to develop novel protein antagonists of P-selectin adhesion as anti- inflammatory therapeutics. Blocking P-selectin adhesion is particularly attractive because this adhesion mediates leukocyte rolling which occurs early in the inflammatory cascade before extensive tissue damage caused by the amplification of inflammation by proinflammatory cytokines. Currently, no subnanomolar antagonists of selectin adhesion are available. The low affinity of current antagonists results in the need for frequent administration and large doses in order to obtain inhibition. High affinity antagonists are desirable because they can be administered in smaller amounts thus reducing the risk of harmful side effects and reducing production costs. Our approach for developing high affinity antagonists is to combine error prone PCR and in vivo homologous recombination to mimic in yeast the broad spectrum of mutagenic strategies exploited by B cells such as somatic hypermutation, receptor revision (... CDR replacement), receptor editing (chain shuffling), and amino acid insertions and deletions. Together with yeast surface display and flow cytometric screening (FACS), this approach has been used to effect at least a five order of magnitude affinity improvement in a single chain antibody (scFv) directed against the N-terminal 19 amino acids of P-selectin glycoprotein ligand- 1 (PSGL- 1). Three rounds of engineering were performed after an initial pool of binders was isolated from a non-immune scFv library. Chain shuffling was found to be important for generating an improved mutant in the first round of engineering.(Cont.) For the final round of engineering, four different libraries were generated: one with random mutations, one with preferential replacement of the ... CDR1, one with preferential replacement of the ... CDR1 and the ... CDR2, and one with preferential replacement of the light chain. All of these methods produced two order of magnitude affinity improvements except the light chain exchange library. However, the CDR exchange libraries gave equivalent affinity improvement despite the fact that they were 77 fold smaller than the random mutagenic library. In addition, an insertion in CDR2 of the VH was isolated in the best binder from both of the CDR exchange libraries and this mutation could not have been found through random mutagenesis. These results suggest that chain shuffling is best used when the affinity of the antibody to be matured is weak (> 1 [mu] M). In addition, receptor revision is an equally robust method as random mutagensis for the generation of ultra-high affinity binders. The best antibody from the library with preferential replacement of ... CDR1 and ... CDR2 was converted to an IgG and characterized. It was found to better inhibit P-selectin binding to PSGL-1 than the commercially available antibody KPLI in a static adhesion assay and an in vitro rolling assay. Our integrated approach, made possible by in vivo homologous recombination in yeast, decreases the likelihood of convergence upon a single high affinity solution and increases the probability of obtaining an antibody with desired secretory properties and therapeutic potential. This facile method for combining all the mutational strategies used in nature should prove as a valuable tool in the antibody engineering field.by Jeffrey Seth Swers.Ph.D

Rolling Adhesion of Yeast Engineered to Express Cell Adhesion Molecules

Selectins are cell adhesion molecules that mediate capture of leukocytes on vascular endothelium as an essential component of the inflammatory response. Here we describe a method for yeast surface display of selectins, together with a functional assay that measures rolling adhesion of selectin-expressing yeast on a ligand-coated surface. E-selectin-expressing yeast roll specifically on surfaces bearing sialyl-Lewisx ligands. Observation of yeast rolling dynamics at various stages of their life cycle indicates that the kinematics of yeast motion depends on the ratio of the bud radius to the parent radius (B/P). Large-budded yeast walk across the surface, alternately pivoting about bud and parent. Small-budded yeast wobble across the surface, with bud pivoting about parent. Tracking the bud location of budding yeast allows measurement of the angular velocity of the yeast particle. Comparison of translational and angular velocities of budding yeast demonstrates that selectin-expressing cells are rolling rather than slipping across ligand-coated surfaces

Descriptive and Substantive Representation in Congress: Evidence from 80,000 Congressional Inquiries

A vast literature debates the efficacy of descriptive representation in legislatures. Though studies argue it influences how communities are represented through constituency service, they are limited since legislators’ service activities are unobserved. Using Freedom of Information Act (FOIA) requests, we collected 88,000 records of communication between members of the U.S. Congress and federal agencies during the 108th–113th Congresses. These legislative interventions allow us to examine members’ “follow‐through” with policy implementation. We find that women, racial/ethnic minorities, and veterans are more likely to work on behalf of constituents with whom they share identities. Including veterans offers leverage in understanding the role of political cleavages and shared experiences. Our findings suggest that shared experiences operate as a critical mechanism for representation, that a lack of political consensus is not necessary for substantive representation, and that the causal relationships identified by experimental work have observable implications in the daily work of Congress.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150606/1/ajps12443-sup-0001-SuppMat.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150606/2/ajps12443.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150606/3/ajps12443_am.pd

Untangling the Causal Effects of Sex on Judging

We explore the role of sex in judging by addressing two questions of long-standing interest to political scientists: whether and in what ways male and female judges decide cases distinctly—“individual effects”—and whether and in what ways serving with a female judge causes males to behave differently—“panel effects.” While we attend to the dominant theoretical accounts of why we might expect to observe either or both effects, we do not use the predominant statistical tools to assess them. Instead, we deploy a more appropriate methodology: semiparametric matching, which follows from a formal framework for causal inference. Applying matching methods to 13 areas of law, we observe consistent gender effects in only one—sex discrimination. For these disputes, the probability of a judge deciding in favor of the party alleging discrimination decreases by about 10 percentage points when the judge is a male. Likewise, when a woman serves on a panel with men, the men are significantly more likely to rule in favor of the rights litigant. These results are consistent with an informational account of gendered judging and are inconsistent with several othersPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116101/1/ajps10.pd

High-resolution profiling of homing endonuclease binding and catalytic specificity using yeast surface display

Experimental analysis and manipulation of protein–DNA interactions pose unique biophysical challenges arising from the structural and chemical homogeneity of DNA polymers. We report the use of yeast surface display for analytical and selection-based applications for the interaction between a LAGLIDADG homing endonuclease and its DNA target. Quantitative flow cytometry using oligonucleotide substrates facilitated a complete profiling of specificity, both for DNA-binding and catalysis, with single base pair resolution. These analyses revealed a comprehensive segregation of binding specificity and affinity to one half of the pseudo-dimeric interaction, while the entire interface contributed specificity at the level of catalysis. A single round of targeted mutagenesis with tandem affinity and catalytic selection steps provided mechanistic insights to the origins of binding and catalytic specificity. These methods represent a dynamic new approach for interrogating specificity in protein–DNA interactions