Connecting the Sequence-Space of Bacterial Signaling Proteins to Phenotypes Using Coevolutionary Landscapes.

Two-component signaling (TCS) is the primary means by which bacteria sense and respond to the environment. TCS involves two partner proteins working in tandem, which interact to perform cellular functions whereas limiting interactions with non-partners (i.e., cross-talk). We construct a Potts model for TCS that can quantitatively predict how mutating amino acid identities affect the interaction between TCS partners and non-partners. The parameters of this model are inferred directly from protein sequence data. This approach drastically reduces the computational complexity of exploring the sequence-space of TCS proteins. As a stringent test, we compare its predictions to a recent comprehensive mutational study, which characterized the functionality of 204 mutational variants of the PhoQ kinase in Escherichia coli We find that our best predictions accurately reproduce the amino acid combinations found in experiment, which enable functional signaling with its partner PhoP. These predictions demonstrate the evolutionary pressure to preserve the interaction between TCS partners as well as prevent unwanted cross-talk. Further, we calculate the mutational change in the binding affinity between PhoQ and PhoP, providing an estimate to the amount of destabilization needed to disrupt TCS.

Estimation of protein and domain interactions in the switching motility system of Myxococcus xanthus.

The gram-negative myxobacterium Myxococcus xanthus is equipped with an interesting motility system that allows it to reverse direction on average every 8 minutes by switching the construction of two motility engines at the ends of this rod-shaped bacterium. While the mechanisms responsible for timing and engine construction/deconstruction are relatively well understood, there are several competing hypotheses as to how they are coupled together. In this paper we examine the evidence for protein interactions underlying these possible couplings using a novel framework consisting of a probabilistic model describing protein and domain interactions and a belief propagation inference algorithm. When provided with large amount of indirect pieces of information, such as high-throughput experiment results, and protein structures, we can reliably determine the relative likelihoods of these hypotheses, even though each individual piece of evidence by itself has very limited reliability. The same framework can be used to map large protein and domain interaction networks in myxobacteria and other organisms.

Comparison of parents' expectations and importance ratings for specific aspects of childbirth.

We examined parents' expectations of many aspects of the birth experience and compared them with the importance they attached to these aspects. Expectation was defined as a respondent's rating that a given practice would be reality, and importance was defined as a respondent's rating of the personal importance of a practice were all options possible. Subjects in the last 6 to 8 weeks of pregnancy were asked by their obstetricians to complete a questionnaire; 231 mothers and 227 fathers responded, for a response rate of 95%. In each of six subcategories parents' importance ratings significantly exceeded their expectation ratings. Certain items were rated as relatively less important postnatally than prenatally and by multigravid women than by primigravid women. Parents' perceptions of available options reflect consistent discrepancy with what they wish were possible. However, increased efforts to inform parents of existing options and to provide the rationale for specific practices may reduce the discrepancy between importance and expectations. This would in turn heighten the likelihood of a psychologically positive birth experience for parents.

Adrenocortical function studies during the normal menstrual cycle and in women receiving norethindrone with and without mestranol.

PIP: Adrenocortical function was studied in 10 women receiving norethindrone 2 mg plus mestranol 100 mcg ("maxi" pill) and in 10 women receiving norethindrone .35 mg ("mini" pill) over a 9-month period; plasma cortisol levels (8 a.m. and 3 p.m.), 24-hour urinary cortisol levels, and cortisol secretion rates were measured on Days 10 and 24 of the menstrual cycle. Prior to therapy, during a normal menstrual cycle, 18 of 20 showed a significant peak of luteinizing hormone (LH) which was considered presumptive evidence of ovulation. The 9th cylce during therapy showed: 1) no significant difference between plasma and urinary cortisol on Days 10 and 24, 2) a significant increase in plasma cortisol concentrations at 8 a.m. and 3 p.m. on Days 10 and 24 with the maxi pill in comparison to pretreatment levels, 3) a significant decrease in plasma cortisol at 3 p.m. on Day 10 with the mini pill but no change at other times, 4)a significant decrease in cortisol secretion rate on Day 24 with the maxi pill but no change with the mini pill, and 5) a significant decrease in urinary cortisol levels with the maxi pill on Days 10 and 24 and with the mini pill on Day 10. The mini pill results suggest that progesterone may be responsible for depression of adrenocortical acitivity during the luteal phase. Rise in plasma cortisol concentration probably occurred because of a corresponding rise in corticosteroid-binding globulin concentration induced by the estrogen. Progesterone is likely responsible for halting cortisol production and/or release.^ieng