MONEY ILLUSION, GORMAN AND LAU

Any demand equation satisfying Lau’s (1982) Fundamental Theorem of Exact Aggregation and 0° homogeneity in prices and income will have a Gorman (1981) functional form for each income term. This property does not depend on symmetry or adding up. The implications of this result are illustrated by an extensive example.Demand, exact aggregation, functional form, homogeneity

Structural variants are a major source of gene expression differences in humans and often affect multiple nearby genes

Structural variants (SVs) are an important source of human genome diversity, but their functional effects are poorly understood. We mapped 61,668 SVs in 613 individuals from the GTEx project and measured their effects on gene expression. We estimate that common SVs are causal at 2.66% of eQTLs, a 10.5-fold enrichment relative to their abundance in the genome. Duplications and deletions were the most impactful variant types, whereas the contribution of mobile element insertions was small (0.12% of eQTLs, 1.9-fold enriched). Multitissue analysis of eQTLs revealed that gene-altering SVs show more constitutive effects than other variant types, with 62.09% of coding SV-eQTLs active in all tissues with eQTL activity compared with 23.08% of coding SNV- and indel-eQTLs. Noncoding SVs, SNVs and indels show broadly similar patterns. We also identified 539 rare SVs associated with nearby gene expression outliers. Of these, 62.34% are noncoding SVs that affect gene expression but have modest enrichment at regulatory elements, showing that rare noncoding SVs are a major source of gene expression differences but remain difficult to predict from current annotations. Both common and rare SVs often affect the expression of multiple genes: SV-eQTLs affect an average of 1.82 nearby genes, whereas SNV- and indel-eQTLs affect an average of 1.09 genes, and 21.34% of rare expression-altering SVs show effects on two to nine different genes. We also observe significant effects on rare gene expression changes extending 1 Mb from the SV. This provides a mechanism by which individual SVs may have strong or pleiotropic effects on phenotypic variation

The effects of estradiol-17β on the sex reversal, survival, and growth of green sunfish Lepomis cyanellus

The feminization of green sunfish Lepomis cyanellus could expand their utility as a game fish or aquacultured species by preventing overcrowding and precocious reproduction in stocked systems. Feminization of green sunfish could also help elucidate information on their sex determination system. We report the feminization of green sunfish cohorts via oral administration of estradiol-17β (E2) during early development. A low-dose (100 E2 mg per kg of diet) and a high-dose (150 E2 mg per kg of diet) experimental E2 treatment were fed to juvenile green sunfish from 30 to 90 days post-hatch. Fish were subsequently evaluated for any treatment effect on gonadal development, survival, and growth. Both E2 treatments resulted in 100% feminization, with no morphological or histological differences detected between E2 treated ovaries and those from a control group. The control group was composed mostly of males (82.61%). Overall, there was no effect of E2 on survival (P = 0.310) and growth rate data suggested no statistical differences (P = 0.0805). However, the growth rate of the high-dose group increased slightly higher after the treatment ended than the other treatments (P = 0.042), suggesting that E2 might suppress growth in green sunfish. In addition, the control group did not exhibit a higher survival rate after the treatment period ended (P = 0.266), whereas both E2 treated groups did (P = 0.0003–0.0050). We found that the low dose, 100 E2 mg per kg of diet, was sufficient for fully feminizing green sunfish if administered during development from 30 to 90 days post-hatch and E2 dosages may result in deleterious effects on green sunfish’s health and growth

The Prospect of Detecting Volcanic Signatures on an ExoEarth Using Direct Imaging

The James Webb Space Telescope (JWST) has provided the first opportunity to study the atmospheres of terrestrial exoplanets and estimate their surface conditions. Earth-sized planets around Sun-like stars are currently inaccessible with JWST however, and will have to be observed using the next generation of telescopes with direct imaging capabilities. Detecting active volcanism on an Earth-like planet would be particularly valuable as it would provide insight into its interior, and provide context for the commonality of the interior states of Earth and Venus. In this work we used a climate model to simulate four exoEarths over eight years with ongoing large igneous province eruptions with outputs ranging from 1.8-60 Gt of sulfur dioxide. The atmospheric data from the simulations were used to model direct imaging observations between 0.2-2.0 $\mu$m, producing reflectance spectra for every month of each exoEarth simulation. We calculated the amount of observation time required to detect each of the major absorption features in the spectra, and identified the most prominent effects that volcanism had on the reflectance spectra. These effects include changes in the size of the O$_3$, O$_2$, and H$_2$O absorption features, and changes in the slope of the spectrum. Of these changes, we conclude that the most detectable and least ambiguous evidence of volcanism are changes in both O$_3$ absorption and the slope of the spectrum.Comment: 13 pages, 5 figures, 4 tables, Accepted for publication in AJ (September 26, 2023

Winter 1972

The Mode of Action of Arsenicals in the Soil by Cecil F. Kerr (page 3) The Golf Course Superintendent: A Job Description (5) Factors Affecting Carbohydrate Reserves of Cool Season Turfgrasses by L.J. Zanoni, L. F. Michelson, W.G. COlby, and M. Drake (6) Turf Bulletin\u27s Photo Quiz by Frederick G. Cheney (9) A Close Look at TCDD (10) Environmental News--Environmental Protection Agency Cancels Registration of Herbicide Amitrole (11) Homeowner\u27s Section--Crabgrass in Perspective by R.A. Peters (12) Merion Tees--Maintenance Suggestions (14) Use of Ammonium Sulfate in Fluid Fertilizers by Frank P. Achorn and W.C. Scott, Jr. (15) River Ecology and the Impact on Man (17) To Roll or Not to Roll (18) Editorial--Talkin\u27 Turfie (24

Bipolar disorder with binge eating behavior: a genome-wide association study implicates PRR5-ARHGAP8

Bipolar disorder (BD) is associated with binge eating behavior (BE), and both conditions are heritable. Previously, using data from the Genetic Association Information Network (GAIN) study of BD, we performed genome-wide association (GWA) analyses of BD with BE comorbidity. Here, utilizing data from the Mayo Clinic BD Biobank (969 BD cases, 777 controls), we performed a GWA analysis of a BD subtype defined by BE, and case-only analysis comparing BD subjects with and without BE. We then performed a meta-analysis of the Mayo and GAIN results. The meta-analysis provided genome-wide significant evidence of association between single nucleotide polymorphisms (SNPs) in PRR5-ARHGAP8 and BE in BD cases (rs726170 OR=1.91, P=3.05E-08). In the meta-analysis comparing cases with BD with comorbid BE vs. non-BD controls, a genome-wide significant association was observed at SNP rs111940429 in an intergenic region near PPP1R2P5 (p=1.21E-08). PRR5-ARHGAP8 is a read-through transcript resulting in a fusion protein of PRR5 and ARHGAP8. PRR5 encodes a subunit of mTORC2, a serine/threonine kinase that participates in food intake regulation, while ARHGAP8 encodes a member of the RhoGAP family of proteins that mediate cross-talk between Rho GTPases and other signaling pathways. Without BE information in controls, it is not possible to determine whether the observed association reflects a risk factor for BE in general, risk for BE in individuals with BD, or risk of a subtype of BD with BE. The effect of PRR5-ARHGAP8 on BE risk thus warrants further investigation

Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila

Abstract: Somatic mutations in the mitochondrial genome (mtDNA) have been linked to multiple disease conditions and to ageing itself. In Drosophila, knock-in of a proofreading deficient mtDNA polymerase (POLG) generates high levels of somatic point mutations and also small indels, but surprisingly limited impact on organismal longevity or fitness. Here we describe a new mtDNA mutator model based on a mitochondrially-targeted cytidine deaminase, APOBEC1. mito-APOBEC1 acts as a potent mutagen which exclusively induces C:G>T:A transitions with no indels or mtDNA depletion. In these flies, the presence of multiple non-synonymous substitutions, even at modest heteroplasmy, disrupts mitochondrial function and dramatically impacts organismal fitness. A detailed analysis of the mutation profile in the POLG and mito-APOBEC1 models reveals that mutation type (quality) rather than quantity is a critical factor in impacting organismal fitness. The specificity for transition mutations and the severe phenotypes make mito-APOBEC1 an excellent mtDNA mutator model for ageing research

Exome sequencing of Finnish isolates enhances rare-variant association power.

Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of rare coding variants in clinically relevant quantitative cardiometabolic traits. Exome-wide association studies for 64 quantitative traits identified 26 newly associated deleterious alleles. Of these 26 alleles, 19 are either unique to or more than 20 times more frequent in Finnish individuals than in other Europeans and show geographical clustering comparable to Mendelian disease mutations that are characteristic of the Finnish population. We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power

Protease-sensitive synthetic prions

Prions arise when the cellular prion protein (PrP(C)) undergoes a self-propagating conformational change; the resulting infectious conformer is designated PrP(Sc). Frequently, PrP(Sc) is protease-resistant but protease-sensitive (s) prions have been isolated in humans and other animals. We report here that protease-sensitive, synthetic prions were generated in vitro during polymerization of recombinant (rec) PrP into amyloid fibers. In 22 independent experiments, recPrP amyloid preparations, but not recPrP monomers or oligomers, transmitted disease to transgenic mice (n = 164), denoted Tg9949 mice, that overexpress N-terminally truncated PrP. Tg9949 control mice (n = 174) did not spontaneously generate prions although they were prone to late-onset spontaneous neurological dysfunction. When synthetic prion isolates from infected Tg9949 mice were serially transmitted in the same line of mice, they exhibited sPrP(Sc) and caused neurodegeneration. Interestingly, these protease-sensitive prions did not shorten the life span of Tg9949 mice despite causing extensive neurodegeneration. We inoculated three synthetic prion isolates into Tg4053 mice that overexpress full-length PrP; Tg4053 mice are not prone to developing spontaneous neurological dysfunction. The synthetic prion isolates caused disease in 600-750 days in Tg4053 mice, which exhibited sPrP(Sc). These novel synthetic prions demonstrate that conformational changes in wild-type PrP can produce mouse prions composed exclusively of sPrP(Sc)

A randomized phase 2 study of trastuzumab and pertuzumab (TP) compared to cetuximab and irinotecan (CETIRI) in advanced/metastatic colorectal cancer (mCRC) with HER2 amplification: SWOG S1613

Background: HER2 (ERBB2) over-expression and amplification (HER2+) is seen in a small but distinct subset (2-3%) of mCRC and is enriched in RAS/BRAF wild type (WT) tumors. This subset is characterized by a limited response to anti-epidermal growth factor receptor monoclonal antibodybased (anti-EGFR) therapy and a promising response to dual-HER2 inhibition. Methods: In this multicenter, open label, randomized, phase 2 trial, we enrolled 54 patients with RAS/BRAF WT HER2+ mCRC who had had disease progression after 1 or 2 previous therapies. HER2 status was confirmed centrally with immunohistochemistry (IHC) and in-situ hybridization (ISH). HER2+ was defined as IHC 3+ or 2+ and ISH amplified (dual-probe HER2/CEP17 ratio \u3e 2.0). Patients were then randomly assigned in a 1:1 ratio to receive either TP (trastuzumab [loading 8 mg/kg then 6 mg/kg] + pertuzumab [loading 840 mg then 420 mg] every 3 weeks) or CETIRI (cetuximab 500 mg/m2 + irinotecan 180 mg/m2 every 2 weeks). Crossover was allowed for patients on CETIRI arm to TP (cTP) after progression. Restaging (per RECIST v1.1) was performed at 6 and 12 weeks and then every 8 weeks until progression. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were overall response rate (ORR), overall survival (OS) and safety. Results: A total of 54 (out of planned 62 due to low accrual) patients were randomized to TP (26) and CETIRI (28) between 10/2017 and 12/2021. By 8/18/2022, 20 patients had crossed over to cTP arm. One CETIRI patient was not analyzable. The results for key endpoints by protocol defined stratification factors, prior irinotecan (Piri) (yes or no) and HER2/CEP17 ratio (HCR) (\u3e5 or ≤5), are summarized as of data cut-off of 9/6/2022. PFS did not vary significantly by treatment: medians 4.4 (95%CI: 1.9 - 7.6) months in TP group and 3.7 (95%CI: 1.6 - 6.7) months in CETIRI group (p = 0.35). Grade≥3 adverse events occurred in 23%, 46% and 40% of patients in TP, CETIRI and cTP groups. Conclusions: Dual-HER2 inhibition with TP appears to be a safe and effective treatment option for patients with RAS/BRAF WT HER2+ mCRC with a promising response rate of31%.Higher level of HER2 amplification may provide a greater degree of clinical benefit from TP compared to CETIRI. Future correlative efforts will explore biomarkers of response/resistance with this strategy