Structure of catalytic domain of Matriptase in complex with Sunflower trypsin inhibitor-1

Seed storage proteins are both an important source of nutrition for humans and essential for seedling establishment. Interestingly, unusual napin-type 2S seed storage albumin precursors in sunflowers contain a sequence that is released as a macrocyclic peptide during post-translational processing. The mechanism by which such peptides emerge from linear precursor proteins has received increased attention; however, the structural characterization of intact precursor proteins has been limited. Here, we report the 3D NMR structure of the Helianthus annuus PawS1 (preproalbumin with sunflower trypsin inhibitor-1) and provide new insights into the processing of this remarkable dual-destiny protein. In seeds, PawS1 is matured by asparaginyl endopeptidases (AEPs) into the cyclic peptide SFTI-1 (sunflower trypsin inhibitor-1) and a heterodimeric 2S albumin. The structure of PawS1 revealed that SFTI-1 and the albumin are independently folded into well-defined domains separated by a flexible linker. PawS1 was cleaved in vitro with recombinant sunflower HaAEP1 and in situ using a sunflower seed extract in a way that resembled the expected in vivo cleavages. Recombinant HaAEP1 cleaved PawS1 at multiple positions, and in situ, its flexible linker was removed, yielding fully mature heterodimeric albumin. Liberation and cyclization of SFTI-1, however, was inefficient, suggesting that specific seed conditions or components may be required for in vivo biosynthesis of SFTI-1. In summary, this study has revealed the 3D structure of a macrocyclic precursor protein and provided important mechanistic insights into the maturation of sunflower proalbumins into an albumin and a macrocyclic peptide

python-ags4: A Python library to read, write, and validate AGS4 geodata files

Data gathered from geotechnical, geoenvironmental, and geophysical investigations can be broadly described as “geodata”. The AGS4 data format (Association of Geotechnical and Geoenvironmental Specialists, 2011, 2017, 2021b, 2022) is one of the most widely used data transmittal formats for geodata and is used across the world. It is a plain text format consisting of multiple tables of comma-separated values, tied together with a robust data schema and a comprehensive suite of validation rules. The basic structure of an AGS4 file is shown in Figure 1. Figure 1: Simplified schematic of AGS4 data structure Source: Association of Geotechnical and Geoenvironmental Specialists (2022) python-ags4 is a Python library that provides functionality to read, write, and validate AGS4 geodata files. It provides users with a gateway to access the full power of the Python ecosystem to explore, analyze, and visualize geodata. Pandas DataFrame (The pandas development team, 2020) is the primary data structure used within the library, therefore it can handle relatively large datasets reasonably fast. The data validation module checks the file for compliance with the validation rules and provides a detailed error report. An example error report is shown in Figure 2

Addressing the Need for Training More School Psychologists to Serve Toddlers and Preschoolers with Autism Spectrum Disorders

The prevalence of autism spectrum disorder (ASD) has risen significantly in the past two decades. Unfortunately, there is a shortage of mental health providers who have specialized training in delivering evidenced-based services to this population. Early intensive behavioral intervention (EIBI) is an evidenced-based treatment recommended for toddlers with ASD, and school psychologists are uniquely positioned to help children with ASD receive it. However, many school psychologists do not receive adequate training in this subspecialty. This paper makes recommendations to school psychology training programs about how to add or improve training in this subspecialty based on the results of an Office of Special Education Programs grant-funded ASD training program which involved collaboration between a NASP-approved and APA-accredited school psychology training program and a community-based early intensive behavioral intervention (EIBI) clinic. The grant supported development of an interdisciplinary didactic and clinical training program to increase the ASD knowledge, skills, and competencies of school psychology graduate students, with the broader goals of developing a replicable training model and increasing the workforce of trained providers for this underserved population. Fifteen graduate students completed the training program. Outcomes related to trainee knowledge, skills, and competencies, trainee satisfaction, and lessons learned over time analyzed within a logic model that guided the project’s development and execution can be informative for other school psychology programs undertaking training in this subspecialty

Dynamic partnership: A new approach to EM technology commercialization and deployment

The task of restoring nuclear defense complex sites under the U.S. Department of Energy (DOE) Environmental Management (EM) Program presents an unprecedented challenge to the environmental restoration community. Effective and efficient cleanup requires the timely development or modification of novel cleanup technologies applicable to radioactive wastes. Fostering the commercialization of these innovative technologies is the mission of EM-50, the EM Program Office of Science and Technology. However, efforts are often arrested at the {open_quotes}valley of death,{close_quotes} the general term for barriers to demonstration, commercialization, and deployment. The Energy & Environmental Research Center (EERC), a not-for-profit, contract-supported organization focused on research, development, demonstration, and commercialization (RDD&C) of energy and environmental technologies, is in the second year of a cooperative agreement with the U.S. Department of Energy (DOE) Morgantown Energy Technology Center (METC) designed to deliver EM technologies into the commercial marketplace through a unique combination of technical support, real-world demonstration, and brokering. This paper profiles this novel approach, termed {open_quotes}Dynamic Partnership,{close_quotes} and reviews the application of this concept to the ongoing commercialization and deployment of four innovative cleanup technologies. 2 tabs

Insufficient Production and Tissue Delivery of CD4+Memory T Cells in Rapidly Progressive Simian Immunodeficiency Virus Infection

The mechanisms linking human immunodeficiency virus replication to the progressive immunodeficiency of acquired immune deficiency syndrome are controversial, particularly the relative contribution of CD4+ T cell destruction. Here, we used the simian immunodeficiency virus (SIV) model to investigate the relationship between systemic CD4+ T cell dynamics and rapid disease progression. Of 18 rhesus macaques (RMs) infected with CCR5-tropic SIVmac239 (n = 14) or CXCR4-tropic SIVmac155T3 (n = 4), 4 of the former group manifested end-stage SIV disease by 200 d after infection. In SIVmac155T3 infections, naive CD4+ T cells were dramatically depleted, but this population was spared by SIVmac239, even in rapid progressors. In contrast, all SIVmac239-infected RMs demonstrated substantial systemic depletion of CD4+ memory T cells by day 28 after infection. Surprisingly, the extent of CD4+ memory T cell depletion was not, by itself, a strong predictor of rapid progression. However, in all RMs destined for stable infection, this depletion was countered by a striking increase in production of short-lived CD4+ memory T cells, many of which rapidly migrated to tissue. In all rapid progressors (P < 0.0001), production of these cells initiated but failed by day 42 of infection, and tissue delivery of new CD4+ memory T cells ceased. Thus, although profound depletion of tissue CD4+ memory T cells appeared to be a prerequisite for early pathogenesis, it was the inability to respond to this depletion with sustained production of tissue-homing CD4+ memory T cells that best distinguished rapid progressors, suggesting that mechanisms of the CD4+ memory T cell generation play a crucial role in maintaining immune homeostasis in stable SIV infection

Case Report: A myxoma with a far reach

A 73-year-old woman presented to the emergency department with a syncopal episode and a history of dizzy spells. A transthoracic echocardiogram demonstrated a large left atrial mass extending into the right upper pulmonary veins. Subsequently, cardiac magnetic resonance imaging and coronary computed tomography angiography with three-dimensional reconstruction and printing of the heart and mass were performed, which demonstrated a high index of suspicion for an atypical left atrial myxoma. The mass was excised robotically, and the pathology report confirmed a diagnosis of myxoma

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Mutations causing medullary cystic kidney disease type 1 (MCKD1) lie in a large VNTR in MUC1 missed by massively parallel sequencing

While genetic lesions responsible for some Mendelian disorders can be rapidly discovered through massively parallel sequencing (MPS) of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple Mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing, and de novo assembly, we found that each of six MCKD1 families harbors an equivalent, but apparently independently arising, mutation in sequence dramatically underrepresented in MPS data: the insertion of a single C in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (~1.5-5 kb), GC-rich (>80%), coding VNTR in the mucin 1 gene. The results provide a cautionary tale about the challenges in identifying genes responsible for Mendelian, let alone more complex, disorders through MPS