Ethylene-mediated nitric oxide depletion pre-adapts plants to hypoxia stress

Timely perception of adverse environmental changes is critical for survival. Dynamic changes in gases are important cues for plants to sense environmental perturbations, such as submergence. In Arabidopsis thaliana, changes in oxygen and nitric oxide (NO) control the stability of ERFVII transcription factors. ERFVII proteolysis is regulated by the N-degron pathway and mediates adaptation to flooding-induced hypoxia. However, how plants detect and transduce early submergence signals remains elusive. Here we show that plants can rapidly detect submergence through passive ethylene entrapment and use this signal to pre-adapt to impending hypoxia. Ethylene can enhance ERFVII stability prior to hypoxia by increasing the NO-scavenger PHYTOGLOBIN1. This ethylene-mediated NO depletion and consequent ERFVII accumulation pre-adapts plants to survive subsequent hypoxia. Our results reveal the biological link between three gaseous signals for the regulation of flooding survival and identifies key regulatory targets for early stress perception that could be pivotal for developing flood-tolerant crops

Data analysis strategies for the Accelerating Medicines Partnership® Schizophrenia Program.

The Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ) project assesses a large sample of individuals at clinical high-risk for developing psychosis (CHR) and community controls. Subjects are enrolled in 43 sites across 5 continents. The assessments include domains similar to those acquired in previous CHR studies along with novel domains that are collected longitudinally across a period of 2 years. In parallel with the data acquisition, multidisciplinary teams of experts have been working to formulate the data analysis strategy for the AMP SCZ project. Here, we describe the key principles for the data analysis. The primary AMP SCZ analysis aim is to use baseline clinical assessments and multimodal biomarkers to predict clinical endpoints of CHR individuals. These endpoints are defined for the AMP SCZ study as transition to psychosis (i.e., conversion), remission from CHR syndrome, and persistent CHR syndrome (non-conversion/non-remission) obtained at one year and two years after baseline assessment. The secondary aim is to use longitudinal clinical assessments and multimodal biomarkers from all time points to identify clinical trajectories that differentiate subgroups of CHR individuals. The design of the analysis plan is informed by reviewing legacy data and the analytic approaches from similar international CHR studies. In addition, we consider properties of the newly acquired data that are distinct from the available legacy data. Legacy data are used to assist analysis pipeline building, perform benchmark experiments, quantify clinical concepts and to make design decisions meant to overcome the challenges encountered in previous studies. We present the analytic design of the AMP SCZ project, mitigation strategies to address challenges related to the analysis plan, provide rationales for key decisions, and present examples of how the legacy data have been used to support design decisions for the analysis of the multimodal and longitudinal data. Watch Prof. Ofer Pasternak discuss his work and this article: https://vimeo.com/1023394132?share=copy#t=0

Cognitive assessment in the Accelerating Medicines Partnership® Schizophrenia Program:harmonization priorities and strategies in a diverse international sample

Cognitive impairment occurs at higher rates in individuals at clinical high risk (CHR) for psychosis relative to healthy peers, and it contributes unique variance to multivariate prediction models of transition to psychosis. Such impairment is considered a core biomarker of schizophrenia. Thus, cognition is a key domain measured in the Accelerating Medicines Partnership® program for Schizophrenia (AMP SCZ initiative). The aim of this paper is to describe the rationale, processes, considerations, and final harmonization of the cognitive battery used in AMP SCZ across the two data collection networks. This battery comprises tests of general intellect and specific cognitive domains. We estimate premorbid intelligence at baseline and measure current intelligence at baseline and 2 years. Eight tests from the Penn Computerized Neurocognitive Battery (PennCNB), which measure verbal learning and memory, sensorimotor ability, attention, emotion recognition, working memory, processing speed, verbal memory, visual memory, and motor speed are administered repeatedly at baseline, and four follow-up timepoints over 2 years.</p

Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ): Rationale and Study Design of the Largest Global Prospective Cohort Study of Clinical High Risk for Psychosis

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals