Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation

52 Genetic Loci Influencing Myocardial Mass.

BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets

”Osynliga regler på bensinstation” : En studie om applicering av regel kan skapa ordning genom rumsliga element vid vägledning och att förändra människor beteende för illegal parkering på en bensinstation.

Denna kandidatuppsats handlar om informationsdesign med fokus på rumslig design. Syftet med denna studie handlar om att undersöka och förstå människors beteende när det gäller att välja en parkeringsplats. Detta kan påverka trafikstopp och de orienterings strategier som finns på en bensinstation.    I studien har relevant kurslitteratur använts inom informationsdesign som navigationssystem, orienterbarhet, wayfinding/wayshowing, färg och perception som grundteorier. Med kombinerade metoder som omvärldsanalys, platsanalys och kvalitativ intervju har använts genom arbetet. För tas fram ett gestaltningsförslag som eventuell kan lösa de befintliga problem som bensinstationen har, samt en framtiddesign. Gestaltningsförslag innehåller tydliga informationsskyltar såväl som vägmarkeringar, förbättrat trafikflöde och troligtvis minska förvirring samt osäkerhet hos nya- och stamkunder. Med tillämpade regler och riktlinjer skapas en ny rumsupplevelse med ordning och struktur.This candidate's thesis is about information design with a focus on spatial design. The purpose of this study is to research and understand people's behavior, when it comes to choosing a parking space that can affect traffic stops and the orientation strategies at a gas station.   The study has used relevant course literature within informationsdesign field, such as navigation systems, orientability, wayfinding/wayshowing, color and perception as basic theories. Combined methods such as environmental analysis, location analysis and qualitative interview have been used throughout the thesis. To come up with a design proposal that could possibly solve the existing problems the petrol station has. The design proposal included clear information signs as well as visible road markings. This is to improve traffic flow and reduce confusion and uncertainties among new and regular customers. With applied rules and guidelines created a new spatial experience which can contribute order and structure within this area.

”Osynliga regler på bensinstation” : En studie om applicering av regel kan skapa ordning genom rumsliga element vid vägledning och att förändra människor beteende för illegal parkering på en bensinstation.

Denna kandidatuppsats handlar om informationsdesign med fokus på rumslig design. Syftet med denna studie handlar om att undersöka och förstå människors beteende när det gäller att välja en parkeringsplats. Detta kan påverka trafikstopp och de orienterings strategier som finns på en bensinstation.    I studien har relevant kurslitteratur använts inom informationsdesign som navigationssystem, orienterbarhet, wayfinding/wayshowing, färg och perception som grundteorier. Med kombinerade metoder som omvärldsanalys, platsanalys och kvalitativ intervju har använts genom arbetet. För tas fram ett gestaltningsförslag som eventuell kan lösa de befintliga problem som bensinstationen har, samt en framtiddesign. Gestaltningsförslag innehåller tydliga informationsskyltar såväl som vägmarkeringar, förbättrat trafikflöde och troligtvis minska förvirring samt osäkerhet hos nya- och stamkunder. Med tillämpade regler och riktlinjer skapas en ny rumsupplevelse med ordning och struktur.This candidate's thesis is about information design with a focus on spatial design. The purpose of this study is to research and understand people's behavior, when it comes to choosing a parking space that can affect traffic stops and the orientation strategies at a gas station.   The study has used relevant course literature within informationsdesign field, such as navigation systems, orientability, wayfinding/wayshowing, color and perception as basic theories. Combined methods such as environmental analysis, location analysis and qualitative interview have been used throughout the thesis. To come up with a design proposal that could possibly solve the existing problems the petrol station has. The design proposal included clear information signs as well as visible road markings. This is to improve traffic flow and reduce confusion and uncertainties among new and regular customers. With applied rules and guidelines created a new spatial experience which can contribute order and structure within this area.

Prolonged Exposure to Microgravity Reduces Cardiac Contractility and Initiates Remodeling in Drosophila.

Understanding the effects of microgravity on human organs is crucial to exploration of low-earth orbit, the moon, and beyond. Drosophila can be sent to space in large numbers to examine the effects of microgravity on heart structure and function, which is fundamentally conserved from flies to humans. Flies reared in microgravity exhibit cardiac constriction with myofibrillar remodeling and diminished output. RNA sequencing (RNA-seq) in isolated hearts revealed reduced expression of sarcomeric/extracellular matrix (ECM) genes and dramatically increased proteasomal gene expression, consistent with the observed compromised, smaller hearts and suggesting abnormal proteostasis. This was examined further on a second flight in which we found dramatically elevated proteasome aggregates co-localizing with increased amyloid and polyQ deposits. Remarkably, in long-QT causing sei/hERG mutants, proteasomal gene expression at 1g, although less than the wild-type expression, was nevertheless increased in microgravity. Therefore, cardiac remodeling and proteostatic stress may be a fundamental response of heart muscle to microgravity

Δcps1 vaccine protects dogs against experimentally induced coccidioidomycosis

Coccidioidomycosis is a significant health problem of dogs and humans in endemic regions, especially California and Arizona in the U.S. Both species would greatly benefit from a vaccine to prevent this disease. A live avirulent vaccine candidate, Δcps1, was tested for tolerability and efficacy to prevent pulmonary coccidioidomycosis in a canine challenge model. Vaccine injection-site reactions were transient and there were no systemic effects observed. Six of seven vaccine sites tested and all draining lymph nodes were sterile post-vaccination. Following infection with Coccidioides posadasii, strain Silveira, arthroconidia into the lungs, dogs given primary and booster vaccinations had significantly reduced lung fungal burdens (P = 0.0003) and composite disease scores (P = 0.0002) compared to unvaccinated dogs. Dogs vaccinated once had fungal burdens intermediate between those given two doses or none, but disease scores were not significantly different from unvaccinated (P = 0.675). Δcps1 was well-tolerated in the dogs and it afforded a high level of protection when given as prime and boost. These results drive the Δcps1 vaccine toward a licensed veterinary vaccine and support continued development of this vaccine to prevent coccidioidomycosis in humans.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]