The inevitability of unconditionally deleterious substitutions during adaptation

Studies on the genetics of adaptation typically neglect the possibility that a deleterious mutation might fix. Nonetheless, here we show that, in many regimes, the first substitution is most often deleterious, even when fitness is expected to increase in the long term. In particular, we prove that this phenomenon occurs under weak mutation for any house-of-cards model with an equilibrium distribution. We find that the same qualitative results hold under Fisher's geometric model. We also provide a simple intuition for the surprising prevalence of unconditionally deleterious substitutions during early adaptation. Importantly, the phenomenon we describe occurs on fitness landscapes without any local maxima and is therefore distinct from "valley-crossing". Our results imply that the common practice of ignoring deleterious substitutions leads to qualitatively incorrect predictions in many regimes. Our results also have implications for the substitution process at equilibrium and for the response to a sudden decrease in population size.Comment: Corrected typos and minor errors in Supporting Informatio

New York Evidence: 2012 Courtroom Manual (2012)

Table of Contents onlyhttps://digitalcommons.nyls.edu/fac_books/1125/thumbnail.jp

Don\u27t Have a Cow . . . Or The Restatement (Second)

“Don’t have a cow” is not only Bart Simpson’s mantra but also the admonition of the Michigan Supreme Court in Lenawee County Board of Health v. Messerly. For almost a hundred years, law students and lawyers had a cow to instruct them on the law of mistake: Rose II of Aberlone – the cow in Sherwood v. Walker. Most American lawyers and judges have read Sherwood v. Walker in their contracts casebook and/or have heard their contracts professor talk about the Michigan Supreme Court decision in Sherwood v. Walker and Rose II of Aberlone. Lawyers of a certain age remember Professor Brainerd Currie’s 3,544-word rhymed verse poem, “Rose of Aberlone.” Younger lawyers are more likely to recall Professor Carswell’s song on YouTube, “My Rose.” [..

“Don’t Have a Cow” . . . or the Restatement (Second)

“Don’t have a cow” is not only Bart Simpson’s mantra but also the admonition of the Michigan Supreme Court in Lenawee County Board of Health v. Messerly. For almost a hundred years, law students and lawyers had a cow to instruct them on the law of mistake: Rose II of Aberlone – the cow in Sherwood v. Walker. Most American lawyers and judges have read Sherwood v. Walker in their contracts casebook and/or have heard their contracts professor talk about the Michigan Supreme Court decision in Sherwood v. Walker and Rose II of Aberlone. Lawyers of a certain age remember Professor Brainerd Currie’s 3,544-word rhymed verse poem, “Rose of Aberlone.” Younger lawyers are more likely to recall Professor Carswell’s song on YouTube, “My Rose.” [..

Up-Regulated Expression of Extracellular Matrix Remodeling Genes in Phagocytically Challenged Trabecular Meshwork Cells

Cells in the trabecular meshwork (TM), the tissue responsible for draining aqueous humor out of the eye, are known to be highly phagocytic. Phagocytic function in TM cells is thought to play an important role in the normal functioning of the outflow pathway. Dysfunction of phagocytosis could lead to abnormalities of outflow resistance and increased intraocular pressure (IOP). However, the molecular mechanisms triggered by phagocytosis in TM cells are completely unknown.Gene expression profile analysis of human TM cells phagocytically challenged to E. coli or pigment under physiological and oxidative stress environment were performed using Affymetrix U133 plus 2.0 array and analyzed with Genespring GX. Despite the differential biological response elicited by E. coli and pigment particles, a number of genes, including MMP1, MMP3, TNFSF11, DIO2, KYNU, and KCCN2 showed differential expression with both phagocytic ligands in all conditions. Data was confirmed by qPCR in both human and porcine TM cells. Metacore pathway analysis and the usage of recombinant adenovirus encoding the dominant negative mutant of IkB identified NF-κB as a transcription factor mediating the up-regulation of at least MMP1 and MMP3 in TM cells with phagocytosis. In-gel zymography demonstrated increased collagenolytic and caseinolytic activities in the culture media of TM cells challenge to E. coli. In addition, collagenolytic I activity was further confirmed using the self-quenched fluorescent substrate DQ-Collagen I.Here we report for the first time the differential gene expression profile of TM cells phagocytically challenged with either E. coli or pigment. Our data indicate a potential role of phagocytosis in outflow pathway tissue homeostasis through the up-regulation and/or proteolytic activation of extracellular matrix remodeling genes

Nitrogen Partitioning and Transport Through a Subalpine Lake Measured with an Isotope Tracer

We used a stable isotope tracer to measure nitrogen (N) assimilation and transfer through Bull Trout Lake, a 0.3-km2 mountain lake in Idaho, specifically to explore the relative importance of pelagic and benthic producers. was added into the inflow stream above the lake during spring runoff and the resulting mass of tracer was measured within the various ecosystem compartments, including the outflow stream. Although a portion of the moved through the lake quickly due to a low hydraulic residence time during the addition, the tracer was also assimilated rapidly by seston in the water column and at a slower rate by benthic primary producers. By the end of the 10-d injection, 10% of the tracer had left via outflow, 21% was within seston, and 17% was in epiphytes and macrophytes. However, 70 d after the termination of the injection, only ∼ 1% of the tracer remained within seston, whereas 10% was within the benthic primary production compartment as N was recycled within the benthic zone. Quantitative transfer of 15N to invertebrate and fish consumers was low, but turnover in these compartments was slow. A conservative water mass tracer (bromide) indicated that the turnover rate for lake water was 1.8% d−1, whereas 15N turnover for the whole lake was only 0.7% d−1, demonstrating how lakes exert drag on nutrients as they move through the watershed. Due to uptake and storage of nutrients, Bull Trout Lake strongly influenced the timing and magnitude of nutrient export from its watershed

Investment under ambiguity with the best and worst in mind

Recent literature on optimal investment has stressed the difference between the impact of risk and the impact of ambiguity - also called Knightian uncertainty - on investors' decisions. In this paper, we show that a decision maker's attitude towards ambiguity is similarly crucial for investment decisions. We capture the investor's individual ambiguity attitude by applying alpha-MEU preferences to a standard investment problem. We show that the presence of ambiguity often leads to an increase in the subjective project value, and entrepreneurs are more eager to invest. Thereby, our investment model helps to explain differences in investment behavior in situations which are objectively identical