Cotranslational Folding Stimulates Programmed Ribosomal Frameshifting in the Alphavirus Structural Polyprotein

Viruses maximize their genetic coding capacity through a variety of biochemical mechanisms, including programmed ribosomal frameshifting (PRF), which facilitates the production of multiple proteins from a single mRNA transcript. PRF is typically stimulated by structural elements within the mRNA that generate mechanical tension between the transcript and ribosome. However, in this work, we show that the forces generated by the cotranslational folding of the nascent polypeptide chain can also enhance PRF. Using an array of biochemical, cellular, and computational techniques, we first demonstrate that the Sindbis virus structural polyprotein forms two competing topological isomers during its biosynthesis at the ribosome-translocon complex. We then show that the formation of one of these topological isomers is linked to PRF. Coarse-grained molecular dynamics simulations reveal that the translocon-mediated membrane integration of a transmembrane domain upstream from the ribosomal slip site generates a force on the nascent polypeptide chain that scales with observed frameshifting. Together, our results indicate that cotranslational folding of this viral protein generates a tension that stimulates PRF. To our knowledge, this constitutes the first example in which the conformational state of the nascent polypeptide chain has been linked to PRF. These findings raise the possibility that, in addition to RNA-mediated translational recoding, a variety of cotranslational folding or binding events may also stimulate PRF

Cotranslational Folding Stimulates Programmed Ribosomal Frameshifting in the Alphavirus Structural Polyprotein

Viruses maximize their genetic coding capacity through a variety of biochemical mechanisms, including programmed ribosomal frameshifting (PRF), which facilitates the production of multiple proteins from a single mRNA transcript. PRF is typically stimulated by structural elements within the mRNA that generate mechanical tension between the transcript and ribosome. However, in this work, we show that the forces generated by the cotranslational folding of the nascent polypeptide chain can also enhance PRF. Using an array of biochemical, cellular, and computational techniques, we first demonstrate that the Sindbis virus structural polyprotein forms two competing topological isomers during its biosynthesis at the ribosome-translocon complex. We then show that the formation of one of these topological isomers is linked to PRF. Coarse-grained molecular dynamics simulations reveal that the translocon-mediated membrane integration of a transmembrane domain upstream from the ribosomal slip site generates a force on the nascent polypeptide chain that scales with observed frameshifting. Together, our results indicate that cotranslational folding of this viral protein generates a tension that stimulates PRF. To our knowledge, this constitutes the first example in which the conformational state of the nascent polypeptide chain has been linked to PRF. These findings raise the possibility that, in addition to RNA-mediated translational recoding, a variety of cotranslational folding or binding events may also stimulate PRF

pH-responsive supramolecular polymer gel as an enteric elastomer for use in gastric devices

Devices resident in the stomach -- which are used for a variety of clinical applications including nutritional modulation for bariatrics, ingestible electronics for diagnosis and monitoring, and gastric retentive dosage forms for prolonged drug delivery -- typically incorporate elastic polymers to compress the devices during delivery through the esophagus and other narrow orifices in the digestive system. However, in the event of accidental device fracture or migration, the non-degradable nature of these materials risks intestinal obstruction. Here, we show that an elastic, pH-responsive supramolecular gel remains stable and elastic in the acidic environment of the stomach but can be dissolved in the neutral-pH environment of the small and large intestines. In a large animal model, prototype devices with these materials as the key component demonstrated prolonged gastric retention and safe passage. These enteric elastomers should increase the safety profile for a wide range of gastric retentive devices

City of El Campo Downtown Revitalization Plan

The Revitalization Plan for Downtown El Campo is a planning document that provides guidance for the development of Downtown El Campo. This planning document includes an overview and analysis of the existing conditions in the City of El Campo and the El Campo Downtown Revitalization Area, a design proposal with vision, goals, and objectives for enhancing Downtown El Campo and a detailed implementation chapter for successful execution of the plan.This planning document presents the revitalization plan for downtown El Campo, Texas. This document was developed by Texas Target Communities (TTC) in partnership with the City of El Campo. The City of El Campo collaborated with Texas Target Communities in fall 2016 through the summer of 2017 to create a plan for revitalization of downtown El Campo. The purpose of the collaboration was to assess current community conditions, develop goals, objectives, and implementation strategies related to future development & growth strategies, through a public participatory process, in order to help guide the future growth of the City

City of El Campo Downtown Revitalization Plan

The Revitalization Plan for Downtown El Campo is a planning document that provides guidance for the development of Downtown El Campo. This planning document includes an overview and analysis of the existing conditions in the City of El Campo and the El Campo Downtown Revitalization Area, a design proposal with vision, goals, and objectives for enhancing Downtown El Campo and a detailed implementation chapter for successful execution of the plan.This planning document presents the revitalization plan for downtown El Campo, Texas. This document was developed by Texas Target Communities (TTC) in partnership with the City of El Campo. The City of El Campo collaborated with Texas Target Communities in fall 2016 through the summer of 2017 to create a plan for revitalization of downtown El Campo. The purpose of the collaboration was to assess current community conditions, develop goals, objectives, and implementation strategies related to future development & growth strategies, through a public participatory process, in order to help guide the future growth of the City

The SPARC Toroidal Field Model Coil Program

The SPARC Toroidal Field Model Coil (TFMC) Program was a three-year effort between 2018 and 2021 that developed novel Rare Earth Yttrium Barium Copper Oxide (REBCO) superconductor technologies and then successfully utilized these technologies to design, build, and test a first-in-class, high-field (~20 T), representative-scale (~3 m) superconducting toroidal field coil. With the principal objective of demonstrating mature, large-scale, REBCO magnets, the project was executed jointly by the MIT Plasma Science and Fusion Center (PSFC) and Commonwealth Fusion Systems (CFS). The TFMC achieved its programmatic goal of experimentally demonstrating a large-scale high-field REBCO magnet, achieving 20.1 T peak field-on-conductor with 40.5 kA of terminal current, 815 kN/m of Lorentz loading on the REBCO stacks, and almost 1 GPa of mechanical stress accommodated by the structural case. Fifteen internal demountable pancake-to-pancake joints operated in the 0.5 to 2.0 nOhm range at 20 K and in magnetic fields up to 12 T. The DC and AC electromagnetic performance of the magnet, predicted by new advances in high-fidelity computational models, was confirmed in two test campaigns while the massively parallel, single-pass, pressure-vessel style coolant scheme capable of large heat removal was validated. The REBCO current lead and feeder system was experimentally qualified up to 50 kA, and the crycooler based cryogenic system provided 600 W of cooling power at 20 K with mass flow rates up to 70 g/s at a maximum design pressure of 20 bar-a for the test campaigns. Finally, the feasibility of using passive, self-protection against a quench in a fusion-scale NI TF coil was experimentally assessed with an intentional open-circuit quench at 31.5 kA terminal current.Comment: 17 pages 9 figures, overview paper and the first of a six-part series of papers covering the TFMC Progra

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The prevalence and characteristics of dual PharmD/MPH programs offered at US colleges and schools of pharmacy

Objective. To assess the prevalence and characteristics of curriculum in dual doctor of pharmacy (PharmD)/master of public health (MPH) degree programs offered by US pharmacy programs. Methods. An 18-item survey instrument was developed and distributed online to faculty members at US colleges and schools of pharmacy. Results. Of the 110 colleges and schools that responded, 23 (21%) offered a PharmD/MPH degree. Common characteristics of these 23 programs included current PharmD program structure (3 1 1 year), early curricular recruitment, small enrollment, and interdisciplinary coursework occurring online and in the classroom. The impact of the dual degree on the curriculum and longevity of the dual-degree programs varied. About 55% of responding programs without a formal dual-degree program reported that additional public health training was available. Conclusion. Twenty-one percent of colleges and schools of pharmacy offer a combined PharmD/MPH dual degree. Most programs required an additional 1 or 2 semesters to complete both degrees