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Scholarly Works (5 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2014)

Since World War II, less than a third of all interstate wars have ended in peace treaties. Instead of countries making formal concessions, fighting often ends with cease-fires that leave forces in place without belligerents resolving their underlying conflict. Before World War II, however, fighting was usually quickly followed by a peace accord, in which defeated countries formally renounced political claims--usually regarding sovereignty over territory. So why do adversaries no longer end hostilities with peace accords, opting instead for long-term cease-fire agreements?

I contend that as the territorial integrity norm became increasingly robust, it weakened the victor's outside option and strengthening the bargaining position of the defeated by making unilateral annexation of conquered territory far more costly. At the same time, the norm made formal concessions far more permanent, as the defeated could no longer renege and re-conquer lost territory without incurring substantial costs for violating that same norm. Thus, the territorial integrity norm, precisely by making peace deal agreements more credible, made them harder to reach.

After exploring the historical development of the territorial integrity norm, I conduct quantitative tests of my theory using an original dataset I constructed for all interstate wars fought from 1816-2007. I find that neighboring states with settled boundaries before hostilities began are far more likely to sign peace agreements--and do so more quickly--than states with ex ante contested borders. Prior to the advent of this norm (i.e. before 1919), however, the opposite was true: having settled boundaries actually reduced the likelihood of signing a peace accord. I also find that the territorial integrity norm altered the terms of peace. Historically, peace accords granted winners new territory; but under the territorial integrity norm, peace accords now generally return belligerents to international (or antebellum) borders, or alternatively refer the dispute to third party arbitration.

If the territorial integrity norm matters, then strategically-minded states should anticipate no longer being able to invade their neighbors in order to conquer their territory. Testing this proposition for all neighboring countries from 1816-2001, I find as the norm became more robust, neighboring states with settled borders have become far less likely to go to war than similar neighbors with contested borders.

  • 4 supplemental PDFs
Cover page: The Vanishing Peace: Why Belligerents are Increasingly Reluctant to Make Formal Concessions
  • Article
  • Peer Reviewed
International Journal of Comparative Psychology, Volume 35 (2023)
Identifying meaningful vocalizations in nonhuman animals can help explain the evolution of human communications. However, non-speech-like sounds, including laughter equivalents, are not well studied, although they may be meaningful. In this pilot study we investigate whether dogs perform a domain-specific pant during play by capturing vocalizations and behaviors during three interactions: training, play, and rest. Sixteen human and dog dyads participated in a session that included all three interactions in the same order: training, play, rest. During these sessions, each partner wore wireless microphones that transmitted to a receiver and digital recorder, while a standalone digital camera captured video of the interactions. A one-way ANOVA demonstrates that dogs do perform a domain-specific "play pant," which was almost completely absent during training and rest. These vocalizations mostly co-occurred with play behaviors (e.g., play bow) or tickling and cuddling. These preliminary findings suggest that a laugh-like play pant is used by dogs during play; future research should explore other interspecific acoustic signals as derived from conspecific signals and having communicative function.
    Cover page: Dogs produce distinctive play pants: Confirming SimonetCreative Commons 'BY' version 4.0 license
    • Article
    • Peer Reviewed
    LBL Publications (2020)
    CTX-M β-lactamases are widespread in Gram-negative bacterial pathogens and provide resistance to the cephalosporin cefotaxime but not to the related antibiotic ceftazidime. Nevertheless, variants have emerged that confer resistance to ceftazidime. Two natural mutations, causing P167S and D240G substitutions in the CTX-M enzyme, result in 10-fold increased hydrolysis of ceftazidime. Although the combination of these mutations would be predicted to increase ceftazidime hydrolysis further, the P167S/D240G combination has not been observed in a naturally occurring CTX-M variant. Here, using recombinantly expressed enzymes, minimum inhibitory concentration measurements, steady-state enzyme kinetics, and X-ray crystallography, we show that the P167S/D240G double mutant enzyme exhibits decreased ceftazidime hydrolysis, lower thermostability, and decreased protein expression levels compared with each of the single mutants, indicating negative epistasis. X-ray structures of mutant enzymes with covalently trapped ceftazidime suggested that a change of an active-site Ω-loop to an open conformation accommodates ceftazidime leading to enhanced catalysis. 10-μs molecular dynamics simulations further correlated Ω-loop opening with catalytic activity. We observed that the WT and P167S/D240G variant with acylated ceftazidime both favor a closed conformation not conducive for catalysis. In contrast, the single substitutions dramatically increased the probability of open conformations. We conclude that the antagonism is due to restricting the conformation of the Ω-loop. These results reveal the importance of conformational heterogeneity of active-site loops in controlling catalytic activity and directing evolutionary trajectories.
      Cover page: Antagonism between substitutions in β-lactamase explains a path not taken in the evolution of bacterial drug resistance.
      • Article
      • Peer Reviewed
      LBL Publications (2020)
      CTX-M β-lactamases are widespread in Gram-negative bacterial pathogens and provide resistance to the cephalosporin cefotaxime but not to the related antibiotic ceftazidime. Nevertheless, variants have emerged that confer resistance to ceftazidime. Two natural mutations, causing P167S and D240G substitutions in the CTX-M enzyme, result in 10-fold increased hydrolysis of ceftazidime. Although the combination of these mutations would be predicted to increase ceftazidime hydrolysis further, the P167S/D240G combination has not been observed in a naturally occurring CTX-M variant. Here, using recombinantly expressed enzymes, minimum inhibitory concentration measurements, steady-state enzyme kinetics, and X-ray crystallography, we show that the P167S/D240G double mutant enzyme exhibits decreased ceftazidime hydrolysis, lower thermostability, and decreased protein expression levels compared with each of the single mutants, indicating negative epistasis. X-ray structures of mutant enzymes with covalently trapped ceftazidime suggested that a change of an active-site Ω-loop to an open conformation accommodates ceftazidime leading to enhanced catalysis. 10-μs molecular dynamics simulations further correlated Ω-loop opening with catalytic activity. We observed that the WT and P167S/D240G variant with acylated ceftazidime both favor a closed conformation not conducive for catalysis. In contrast, the single substitutions dramatically increased the probability of open conformations. We conclude that the antagonism is due to restricting the conformation of the Ω-loop. These results reveal the importance of conformational heterogeneity of active-site loops in controlling catalytic activity and directing evolutionary trajectories.
        Cover page: Antagonism between substitutions in β-lactamase explains a path not taken in the evolution of bacterial drug resistance Epistasis between resistance mutations in β-lactamase
        • Article
        • Peer Reviewed
        LBL Publications (2018)
        The CTX-M β-lactamases have emerged as the most widespread extended-spectrum β-lactamases (ESBLs) in Gram-negative bacteria. These enzymes rapidly hydrolyze cefotaxime, but not the related cephalosporin, ceftazidime. ESBL variants have evolved, however, that provide enhanced ceftazidime resistance. We show here that a natural variant at a nonactive site, i.e. second-shell residue N106S, enhances enzyme stability but reduces catalytic efficiency for cefotaxime and ceftazidime and decreases resistance levels. However, when the N106S variant was combined with an active-site variant, D240G, that enhances enzyme catalytic efficiency, but decreases stability, the resultant double mutant exhibited higher resistance levels than predicted on the basis of the phenotypes of each variant. We found that this epistasis is due to compensatory effects, whereby increased stability provided by N106S overrides its cost of decreased catalytic activity. X-ray structures of the variant enzymes in complex with cefotaxime revealed conformational changes in the active-site loop spanning residues 103-106 that were caused by the N106S substitution and relieve steric strain to stabilize the enzyme, but also alter contacts with cefotaxime and thereby reduce catalytic activity. We noted that the 103-106 loop conformation in the N106S-containing variants is different from that of WT CTX-M but nearly identical to that of the non-ESBL, TEM-1 β-lactamase, having a serine at the 106 position. Therefore, residue 106 may serve as a "switch" that toggles the conformations of the 103-106 loop. When it is serine, the loop is in the non-ESBL, TEM-like conformation, and when it is asparagine, the loop is in a CTX-M-like, cefotaximase-favorable conformation.
          Cover page: Synergistic effects of functionally distinct substitutions in β-lactamase variants shed light on the evolution of bacterial drug resistance
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