Autoimmunity in Arabidopsis acd11 Is Mediated by Epigenetic Regulation of an Immune Receptor

Certain pathogens deliver effectors into plant cells to modify host protein targets and thereby suppress immunity. These target modifications can be detected by intracellular immune receptors, or Resistance (R) proteins, that trigger strong immune responses including localized host cell death. The accelerated cell death 11 (acd11) “lesion mimic” mutant of Arabidopsis thaliana exhibits autoimmune phenotypes such as constitutive defense responses and cell death without pathogen perception. ACD11 encodes a putative sphingosine transfer protein, but its precise role during these processes is unknown. In a screen for lazarus (laz) mutants that suppress acd11 death we identified two genes, LAZ2 and LAZ5. LAZ2 encodes the histone lysine methyltransferase SDG8, previously shown to epigenetically regulate flowering time via modification of histone 3 (H3). LAZ5 encodes an RPS4-like R-protein, defined by several dominant negative alleles. Microarray and chromatin immunoprecipitation analyses showed that LAZ2/SDG8 is required for LAZ5 expression and H3 lysine 36 trimethylation at LAZ5 chromatin to maintain a transcriptionally active state. We hypothesize that LAZ5 triggers cell death in the absence of ACD11, and that cell death in other lesion mimic mutants may also be caused by inappropriate activation of R genes. Moreover, SDG8 is required for basal and R protein-mediated pathogen resistance in Arabidopsis, revealing the importance of chromatin remodeling as a key process in plant innate immunity

A Quality Assessment of a Collaborative Model of a Pediatric Antimicrobial Stewardship Program

BACKGROUND: Infectious Diseases Society of America guidelines recommend that key antimicrobial stewardship program (ASP) personnel include an infectious disease (ID) physician leader and dedicated ID-trained clinical pharmacist. Limited resources prompted development of an alternative model by using ID physicians and service-based clinical pharmacists at a pediatric hospital. The aim of this study was to analyze the effectiveness and impact of this alternative ASP model. METHODS: The collaborative ASP model incorporated key strategies of education, antimicrobial restriction, day 3 audits, and practice guidelines. High-use and/or high-cost antimicrobial agents were chosen with audits targeting vancomycin, caspofungin, and meropenem. The electronic medical record was used to identify patients requiring day 3 audits and to communicate ASP recommendations. Segmented regression analyses were used to analyze quarterly antimicrobial agent prescription data for the institution and selected services over time. RESULTS: Initiation of ASP and day 3 auditing was associated with blunting of a preexisting increasing trend for caspofungin drug starts and use and a significant downward trend for vancomycin drug starts (relative change -12%) and use (-25%), with the largest reduction in critical care areas. Although meropenem use was already low due to preexisting requirements for preauthorization, a decline in drug use (-31%, P = .021) and a nonsignificant decline in drug starts (-21%, P = .067) were noted. A 3-month review of acceptance of ASP recommendations found rates of 90%, 93%, and 100% for vancomycin, caspofungin, and meropenem, respectively. CONCLUSIONS: This nontraditional ASP model significantly reduced targeted drug usage demonstrating acceptance of integration of service-based clinical pharmacists and ID consultants

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Origin of an Alternative Genetic Code in the Extremely Small and GC–Rich Genome of a Bacterial Symbiont

The genetic code relates nucleotide sequence to amino acid sequence and is shared across all organisms, with the rare exceptions of lineages in which one or a few codons have acquired novel assignments. Recoding of UGA from stop to tryptophan has evolved independently in certain reduced bacterial genomes, including those of the mycoplasmas and some mitochondria. Small genomes typically exhibit low guanine plus cytosine (GC) content, and this bias in base composition has been proposed to drive UGA Stop to Tryptophan (Stop→Trp) recoding. Using a combination of genome sequencing and high-throughput proteomics, we show that an α-Proteobacterial symbiont of cicadas has the unprecedented combination of an extremely small genome (144 kb), a GC–biased base composition (58.4%), and a coding reassignment of UGA Stop→Trp. Although it is not clear why this tiny genome lacks the low GC content typical of other small bacterial genomes, these observations support a role of genome reduction rather than base composition as a driver of codon reassignment

Natural Allelic Variation Defines a Role for ATMYC1: Trichome Cell Fate Determination

The molecular nature of biological variation is not well understood. Indeed, many questions persist regarding the types of molecular changes and the classes of genes that underlie morphological variation within and among species. Here we have taken a candidate gene approach based on previous mapping results to identify the gene and ultimately a polymorphism that underlies a trichome density QTL in Arabidopsis thaliana. Our results show that natural allelic variation in the transcription factor ATMYC1 alters trichome density in A. thaliana; this is the first reported function for ATMYC1. Using site-directed mutagenesis and yeast two-hybrid experiments, we demonstrate that a single amino acid replacement in ATMYC1, discovered in four ecotypes, eliminates known protein–protein interactions in the trichome initiation pathway. Additionally, in a broad screen for molecular variation at ATMYC1, including 72 A. thaliana ecotypes, a high-frequency block of variation was detected that results in >10% amino acid replacement within one of the eight exons of the gene. This sequence variation harbors a strong signal of divergent selection but has no measurable effect on trichome density. Homologs of ATMYC1 are pleiotropic, however, so this block of variation may be the result of natural selection having acted on another trait, while maintaining the trichome density role of the gene. These results show that ATMYC1 is an important source of variation for epidermal traits in A. thaliana and indicate that the transcription factors that make up the TTG1 genetic pathway generally may be important sources of epidermal variation in plants

Electrons, Photons, and Force: Quantitative Single-Molecule Measurements from Physics to Biology

Single-molecule measurement techniques have illuminated unprecedented details of chemical behavior, including observations of the motion of a single molecule on a surface, and even the vibration of a single bond within a molecule. Such measurements are critical to our understanding of entities ranging from single atoms to the most complex protein assemblies. We provide an overview of the strikingly diverse classes of measurements that can be used to quantify single-molecule properties, including those of single macromolecules and single molecular assemblies, and discuss the quantitative insights they provide. Examples are drawn from across the single-molecule literature, ranging from ultrahigh vacuum scanning tunneling microscopy studies of adsorbate diffusion on surfaces to fluorescence studies of protein conformational changes in solution

Navigating New Landscapes: The Contribution of Socio-Legal Scholarship in Mapping the Plurality of International Economic Law and Locating Power in International Economic Relations

The evolution of international economic law in the past two decades has been characterised by the growth and diversification of international economic actors, the expansion in the substantive areas governed by international law, and, crucially, the proliferation of multiple sites of international economic governance. This web of multi-layered international economic governance is, in turn, underpinned by complex dynamics of power which structure the legal and economic relations between the subjects of international economic law and other actors impacted by international legal rules and regulation. The challenge for international legal scholarship lay not only in mapping the multiple sites of international economic governance but also in unmasking the power dynamics inherent in international economic relations. Locating and analysing power relations underlying international economic law is to crucial to understanding the cause and effect of international economic rules and institutions for rulemaking. Conventional legal scholarship with its doctrinal focus, while useful in providing the foundational basis for analysis, cannot adequately capture the complexity of contemporary international economic law. Socio-legal approaches may be able to overcome these epistemological limitations by supplying: a) the methodologies to study international economic law beyond a focus on rules and institutions; and b) the critical theoretical lens to understand the power dynamics inherent in international legal relations. The objective of this paper is twofold: firstly, it will seek to identify the contributions of socio-legal approaches to the study of international economic law; and secondly, it will explore how socio-legal scholarship can provide a methodological and theoretical framework to construct an understanding of the pluralistic nature of international economic regulatory regimes and their underlying dynamics of power. In doing so, the paper will also consider the value of juxtaposing an empirical methodology for mapping legal regimes with a critical normative approach for analysing power relations in international economic law

Track D Social Science, Human Rights and Political Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138414/1/jia218442.pd