Machine learning-guided directed evolution for protein engineering

Machine learning (ML)-guided directed evolution is a new paradigm for biological design that enables optimization of complex functions. ML methods use data to predict how sequence maps to function without requiring a detailed model of the underlying physics or biological pathways. To demonstrate ML-guided directed evolution, we introduce the steps required to build ML sequence-function models and use them to guide engineering, making recommendations at each stage. This review covers basic concepts relevant to using ML for protein engineering as well as the current literature and applications of this new engineering paradigm. ML methods accelerate directed evolution by learning from information contained in all measured variants and using that information to select sequences that are likely to be improved. We then provide two case studies that demonstrate the ML-guided directed evolution process. We also look to future opportunities where ML will enable discovery of new protein functions and uncover the relationship between protein sequence and function.Comment: Made significant revisions to focus on aspects most relevant to applying machine learning to speed up directed evolutio

Modeling Cell-to-Cell Communication Networks Using Response-Time Distributions.

Cell-to-cell communication networks have critical roles in coordinating diverse organismal processes, such as tissue development or immune cell response. However, compared with intracellular signal transduction networks, the function and engineering principles of cell-to-cell communication networks are far less understood. Major complications include: cells are themselves regulated by complex intracellular signaling networks; individual cells are heterogeneous; and output of any one cell can recursively become an additional input signal to other cells. Here, we make use of a framework that treats intracellular signal transduction networks as "black boxes" with characterized input-to-output response relationships. We study simple cell-to-cell communication circuit motifs and find conditions that generate bimodal responses in time, as well as mechanisms for independently controlling synchronization and delay of cell-population responses. We apply our modeling approach to explain otherwise puzzling data on cytokine secretion onset times in T cells. Our approach can be used to predict communication network structure using experimentally accessible input-to-output measurements and without detailed knowledge of intermediate steps

The h-index in Australian Astronomy

The Hirsch (2005) h-index is now widely used as a metric to compare individual researchers. To evaluate it in the context of Australian Astronomy, the h-index for every member of the Astronomical Society of Australia (ASA) is found using NASA's Astrophysics Data System Bibliographic Services (ADS). Percentiles of the h-index distribution are detailed for a variety of categories of ASA members, including students. This enables a list of the top ten Australian researchers by h-index to be produced. These top researchers have h-index values in the range 53<h<77, which is less than that recently reported for the American Astronomical Society Membership. We suggest that membership of extremely large consortia such as SDSS may partially explain the difference. We further suggest that many student ASA members with large h-index values have probably already received their Ph.D.'s and need to upgrade their ASA membership status. To attempt to specify the h-index distribution relative to opportunity, we also detail the percentiles of its distribution by years since Ph.D. award date. This shows a steady increase in h-index with seniority, as can be expected.Comment: Accepted for publication in the Publications of the Astronomical Society of Australi

The Effect of Expansions in Medicaid Eligibility on Hospital Financial Performance: Evidence from Medicare Cost Reports

Expansions in Medicaid eligibility and effects on profitability for different hospitals are examined using data from Medicare Cost Reports and difference-in-differences analysis. Critical access and disproportionate share hospitals are associated with the largest profitability gains from these expansions. Results imply that vulnerable hospitals are affected most by changes to Medicaid

John Rawls’ Theory of Justice and Mixed Conception with a Social Minimum Principle

John Rawls was a political philosopher concerned with social justice, specifically the best way that society could be structured so that individual rights and duties were fairly distributed amongst everyone and division of advantages from social cooperation were optimally determined. He believed that this conception of justice rested in principles that would be agreed upon by free, self-interested and rational persons in a starting position of equality and fairness. The principles of the theory of justice are ones that are meant to enable this group of people to cooperate with each other while recognizing that individuals in the group both share the same interests and have conflicting interests. These principles can be understood as underlying our most strongly held ethical beliefs – the ones that exhibit our ability to make the right moral decisions. This paper explains Rawls’ theory of justice, Justice as Fairness, considers an alternative known as “mixed conception” and offers Rawls’ response to the alternative before delving deeper into the debate to understand whether Rawls’ theory of a “mixed conception” should be chosen for a society. Rawls was a notoriously difficult writer so this thesis spends a significant amount of time trying to explicate his views and arguments. With that being said, this thesis does miss out on some key secondary details but hopes to give a clear and compelling picture of his theory, especially the parts that relate to the debate. The debate centers on the choice between the difference principle, which calls for society to maximize the prospects of the least advantaged, and the social minimum principle, which has society set a social minimum that would allow citizens to lead decent lives and take measures necessary to ensure everyone can reach that minimum. In the end, I reach the conclusion that the social minimum principle, in combination with some of Rawls’ other principles, should be used as one of the main principles of justice in society

Mass Media and Aspiration Manipulation: An Experiment Altering Preferences Over Goals

Mass media consumption has increasingly been found to adversely impact upon psychological states but research has largely neglected the potential influence of media on aspirations. An experiment demonstrates aspirational incomes to be dramatically altered by a textual narrative despite it not presenting any new information. The narrative is constructed to elicit peer comparison effects, a common element of a variety of media formats. The effect of the narrative rapidly dissipates when concentration is redirected to unrelated tasks however, suggesting any influence media presentations have on aspirations may only be fleeting. Nevertheless the results suggest that mass media might currently be augmenting aspirations with potential implications for satisfaction levels, educational attainment and risk preferences. Also the results imply preferences can be altered without new information being presented, a violation of individual decision making theory. An amendment to the theory is proposed