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We argue that party government in the U.S. House of Representatives rests on two pillars: the pursuit of policy goals and the disbursement of particularistic benefits. Existing theories of party government argue that the majority party in the House is often successful in biasing policy outcomes in its favor. In the process, it creates \"policy losers\" among its own members who nevertheless support their party on procedural votes. We posit that the majority party cretes an incentive for even the policy losers to support a procedural coalition through judicious distribution of particularistic benefits that compensates policy losers at a rate commensurate with the policy losses that they suffer. We evaluate our theory empirically using the concept of \"roll rates\" in conjunction with federal domestic outlays data for the period 1983-96. We find that, within the majority party, policy losers are favored in the distribution of \"pork barrel\" spending throughout this period.

Since 1972, campaign spending by House incumbents has skyrocketed, particularly in those districts with marginal support for the incumbent's party. At the same time, parties in the House have become much more cohesive in the way they vote, producing more precise and informative party brands. We argue that these two phenomena are fundamentally linked. As parties have developed more precise reputations, incumbents in these districts must spend much more to attract voters in “marginal” districts, who would be willing to vote for a candidate with the particular incumbent's legislative record, but not the average member of his party. Increasingly precise party reputations provide voters with stronger priors that incumbents are just like the rest of their party, and incumbents in marginal districts must spend more to overcome these beliefs. We demonstrate this using a simple formal model and test it empirically using campaign-spending data from 1972 to 2008.

Success in SNTV requires not merely winning but also coordinating votes. Governing parties often reap coordination advantage thanks to their control of the state and its resources. Since governing parties in authoritarian states enjoy greater control over the state and its resources, we argue that they should also enjoy magnified coordinative advantages in SNTV election. Of course, authoritarian regimes often use state resources to win more votes; we argue that, in SNTV, in addition to winning more votes, those votes can also be distributed more effectively. We demonstrate our claims using election data from both local and national SNTV elections in Taiwan from 1954 to 2005.

We assess the conditions under which majority status generates benefits for incumbent legislators and how these benefits are distributed among members of the majority party. We argue that majority status is valuable only in procedurally partisan chambers; that is, when the majority party monopolizes chamber leadership positions and control of the legislative agenda. Contrary to the existing literature, we also posit that these rewards should be distributed broadly across the majority party. To test our expectations, we utilize 10 recent transitions in the partisan control of U.S. state legislatures and data on campaign contributions. Consistent with our expectations, majority status is valuable, but only in procedurally partisan chambers. Furthermore, the premium in campaign contributions enjoyed by the majority party is primarily distributed to backbenchers, although top party leaders also benefit. These results provide important insights into the distribution of power and influence in U.S. state legislatures.

Early in 1987, to pick a powerful recent example, the Republicans' prospects looked even bleaker than they do today. Democrats had just recaptured the Senate and retained the House, and polls showed that the public had more confidence in them than in the Reagan administration to reduce the federal deficit. The Iran- contra hearings investigating the secret sale of arms to Iran in exchange for the release of hostages and the funneling of the profits to the Nicaraguan contras were the big story, and looked ominous enough to derail Vice President George H.W. Bush's White House aspirations. Then in 1988, Bush handily dispatched Michael S. Dukakis, the Democratic nominee. This wasn't a new story. In 1946, President Harry S. Truman was lower in the polls after his midterm defeat than were George W. Bush, [Bill Clinton] or Ronald Reagan after their midterm losses. Truman was reelected in 1948. Each time since 1948 that one party has retaken one or more houses of Congress and then two years later lost the race for the White House, that party has scapegoated its candidate for the party's sins. But in each case, the congressional party placed onerous burdens on the candidates. Would Truman have won without the \"do-nothing Congress\" to run against in 1948? Would anyone have known about the Dukakis-Willie Horton episode if the congressional Democrats had produced a defensible record on crime in 1988? Or if Democrats hadn't pushed for a welfare bill that looked \"soft on work,\" would \"tax and spend\" have been such a powerful epithet in 1988?

We have reported that autophagy is crucial for clearance of amyloidogenic human IAPP (hIAPP) oligomer, suggesting that an autophagy enhancer could be a therapeutic modality against human diabetes with amyloid accumulation. Here, we show that a recently identified autophagy enhancer (MSL-7) reduces hIAPP oligomer accumulation in human induced pluripotent stem cell-derived β-cells (hiPSC-β-cells) and diminishes oligomer-mediated apoptosis of β-cells. Protective effects of MSL-7 against hIAPP oligomer accumulation and hIAPP oligomer-mediated β-cell death are significantly reduced in cells with knockout of MiTF/TFE family members such as Tfeb or Tfe3 . MSL-7 improves glucose tolerance and β-cell function of hIAPP + mice on high-fat diet, accompanied by reduced hIAPP oligomer/amyloid accumulation and β-cell apoptosis. Protective effects of MSL-7 against hIAPP oligomer-mediated β-cell death and the development of diabetes are also significantly reduced by β-cell-specific knockout of Tfeb . These results suggest that an autophagy enhancer could have therapeutic potential against human diabetes characterized by islet amyloid accumulation. Islet amyloid polypeptide (IAPP) deposition is associated with islet cell loss in diabetes. Here the authors show that a small molecule autophagy enhancer reduces IAPP accumulation in vitro, and also improves glucose tolerance in hIAPP + mice fed high-fat diet, accompanied by reduced hIAPP accumulation, in vivo.

Several Streptococcus pyogenes Cas9 (SpCas9) variants have been developed to improve an enzyme’s specificity or to alter or broaden its protospacer-adjacent motif (PAM) compatibility, but selecting the optimal variant for a given target sequence and application remains difficult. To build computational models to predict the sequence-specific activity of 13 SpCas9 variants, we first assessed their cleavage efficiency at 26,891 target sequences. We found that, of the 256 possible four-nucleotide NNNN sequences, 156 can be used as a PAM by at least one of the SpCas9 variants. For the high-fidelity variants, overall activity could be ranked as SpCas9 ≥ Sniper-Cas9 > eSpCas9(1.1) > SpCas9-HF1 > HypaCas9 ≈ xCas9 >> evoCas9, whereas their overall specificities could be ranked as evoCas9 >> HypaCas9 ≥ SpCas9-HF1 ≈ eSpCas9(1.1) > xCas9 > Sniper-Cas9 > SpCas9. Using these data, we developed 16 deep-learning-based computational models that accurately predict the activity of these variants at any target sequence. Deep-learning models predict the Cas9 variant with optimal activity and specificity for any target sequence.

Base editors, including adenine base editors (ABEs) 1 and cytosine base editors (CBEs) 2 , 3 , are widely used to induce point mutations. However, determining whether a specific nucleotide in its genomic context can be edited requires time-consuming experiments. Furthermore, when the editable window contains multiple target nucleotides, various genotypic products can be generated. To develop computational tools to predict base-editing efficiency and outcome product frequencies, we first evaluated the efficiencies of an ABE and a CBE and the outcome product frequencies at 13,504 and 14,157 target sequences, respectively, in human cells. We found that there were only modest asymmetric correlations between the activities of the base editors and Cas9 at the same targets. Using deep-learning-based computational modeling, we built tools to predict the efficiencies and outcome frequencies of ABE- and CBE-directed editing at any target sequence, with Pearson correlations ranging from 0.50 to 0.95. These tools and results will facilitate modeling and therapeutic correction of genetic diseases by base editing. The activity of adenine or cytosine base editors at specific target nucleotides is predicted computationally.

Crosstalk between liver and skeletal muscle is vital for glucose homeostasis. Hepatokines, liver-derived proteins that play an important role in regulating muscle metabolism, are important to this communication. Here we identify apolipoprotein J (ApoJ) as a novel hepatokine targeting muscle glucose metabolism and insulin sensitivity through a low-density lipoprotein receptor-related protein-2 (LRP2)-dependent mechanism, coupled with the insulin receptor (IR) signaling cascade. In muscle, LRP2 is necessary for insulin-dependent IR internalization, an initial trigger for insulin signaling, that is crucial in regulating downstream signaling and glucose uptake. Of physiologic significance, deletion of hepatic ApoJ or muscle LRP2 causes insulin resistance and glucose intolerance. In patients with polycystic ovary syndrome and insulin resistance, pioglitazone-induced improvement of insulin action is associated with an increase in muscle ApoJ and LRP2 expression. Thus, the ApoJ-LRP2 axis is a novel endocrine circuit that is central to the maintenance of normal glucose homeostasis and insulin sensitivity. Hepatokines are proteins secreted by the liver that can regulate whole body metabolism. Here the authors identify apolipoprotein J as a hepatokine that regulates muscle glucose metabolism and insulin resistance through a low-density lipoprotein receptor-related protein−2 mediated mechanism in mice.

The applications of clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing can be limited by a lack of compatible protospacer adjacent motifs (PAMs), insufficient on-target activity and off-target effects. Here, we report an extensive comparison of the PAM-sequence compatibilities and the on-target and off-target activities of Cas9 from Streptococcus pyogenes (SpCas9) and the SpCas9 variants xCas9 and SpCas9-NG (which are known to have broader PAM compatibility than SpCas9) at 26,478 lentivirally integrated target sequences and 78 endogenous target sites in human cells. We found that xCas9 has the lowest tolerance for mismatched target sequences and that SpCas9-NG has the broadest PAM compatibility. We also show, on the basis of newly identified non-NGG PAM sequences, that SpCas9-NG and SpCas9 can edit six previously unedited endogenous sites associated with genetic diseases. Moreover, we provide deep-learning models that predict the activities of xCas9 and SpCas9-NG at the target sequences. The resulting deeper understanding of the activities of xCas9, SpCas9-NG and SpCas9 in human cells should facilitate their use. A comparison of compatibilities in protospacer adjacent motifs and of on-target and off-target activities of Streptococcus pyogenes Cas9 variants at endogenous sites in human cells enables the editing of new genomic sites associated with genetic diseases.