Glutamate indicators with improved activation kinetics and localization for imaging synaptic transmission

iGluSnFR variants with improved signal-to-noise ratios and targeting to postsynaptic sites have been developed, enabling the analysis of glutamatergic neurotransmission in vivo as illustrated in the mouse visual and somatosensory cortex. The fluorescent glutamate indicator iGluSnFR enables imaging of neurotransmission with genetic and molecular specificity. However, existing iGluSnFR variants exhibit low in vivo signal-to-noise ratios, saturating activation kinetics and exclusion from postsynaptic densities. Using a multiassay screen in bacteria, soluble protein and cultured neurons, we generated variants with improved signal-to-noise ratios and kinetics. We developed surface display constructs that improve iGluSnFR's nanoscopic localization to postsynapses. The resulting indicator iGluSnFR3 exhibits rapid nonsaturating activation kinetics and reports synaptic glutamate release with decreased saturation and increased specificity versus extrasynaptic signals in cultured neurons. Simultaneous imaging and electrophysiology at individual boutons in mouse visual cortex showed that iGluSnFR3 transients report single action potentials with high specificity. In vibrissal sensory cortex layer 4, we used iGluSnFR3 to characterize distinct patterns of touch-evoked feedforward input from thalamocortical boutons and both feedforward and recurrent input onto L4 cortical neuron dendritic spines

Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement

IMPORTANCE: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management. OBJECTIVE: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2. EVIDENCE REVIEW: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence. FINDINGS: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined. CONCLUSIONS AND RELEVANCE: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2

Symbiotic effectiveness in nodulated red clover IV Influence of host factors

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A Statistical Activity Cost Analysis of the Relationship Between Physical and Financial Aspects of Fixed Assets

In this paper, Statistical Activity Cost Analysis (SACA) is used to identify the interaction of mutually dependent physical and financial aspects of a fixed asset-like system configuration. The novelty of the approach is, having established a rational description of the uncertainty inherent in both domains, the analysis of their interaction. Little research to date has investigated the duality of engineering and accounting aspects, in a statistical setting. Our approach is conceptual rather than empirical. We use an illustrative 4-component model, a) to explain the concept of SACA by means of a software demonstration tool, b) to relate financial issues of cost to engineering asset capacity to perform specified tasks, and c) to demonstrate how to produce quantified measures of return and risk, both of which are relevant in areas of life-cycle analysis, budgeting and planning decision-making

Introduction. Ruptures in the Everyday

Ruptures in the Everyday was jointly written by ATG26, a scholarly collective comprising the following authors:Jonathan Bach, Andrew Stuart Bergerson (lead author), Susanne Beer, Mark E. Blum, Michaela Christ, Cristina Cuevas-Wolf, Mary Fulbrook, Eva Giloi, Thomas Gurr, Jason Johnson, Craig Koslofsky, Dani Kranz, Phil Leask, Wendy Lower, Elissa Mailänder, Josie McLellan, Alexandra Oeser, Steve Ostovich, Will Rall, Leonard Schmieding (lead author), Johannes Schwartz, Sara Ann Sewell, Paul Steege, Maximilian Strnad, Julia Timpe, Heléna TóthInternational audienc