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Calcium binding to a remote site can replace magnesium as cofactor for mitochondrial Hsp90 (TRAP1) ATPase activity.
The Hsp90 molecular chaperones are ATP-dependent enzymes that maintain protein homeostasis and regulate many essential cellular processes. Higher eukaryotes have organelle-specific Hsp90 paralogs that are adapted to each subcellular environment. The mitochondrial Hsp90, TNF receptor-associated protein 1 (TRAP1), supports the folding and activity of electron transport components and is increasingly appreciated as a critical player in mitochondrial signaling. Calcium plays a well-known and important regulatory role in mitochondria where it can accumulate to much higher concentrations than in the cytoplasm. Surprisingly, we found here that calcium can replace magnesium, the essential enzymatic cofactor, to support TRAP1 ATPase activity. Anomalous X-ray diffraction experiments revealed a calcium-binding site within the TRAP1 nucleotide-binding pocket located near the ATP α-phosphate and completely distinct from the magnesium-binding site adjacent to the β- and γ-phosphates. In the presence of magnesium, ATP hydrolysis by TRAP1, as with other Hsp90s, was noncooperative, whereas calcium binding resulted in cooperative hydrolysis by the two protomers within the Hsp90 dimer. The structural data suggested a mechanism for this cooperative behavior. Because of the cooperativity, at high ATP concentrations, ATPase activity was higher with calcium, whereas the converse was observed at low ATP concentrations. Integrating these observations, we propose a model in which the divalent cation choice can control switching between noncooperative and cooperative TRAP1 ATPase mechanisms in response to varying ATP concentrations. This switching may facilitate coordination between cellular energetics, mitochondrial signaling, and protein homeostasis via alterations in the TRAP1 ATP-driven cycle and its consequent effects on different mitochondrial clients
Jim Agard: A Retrospective
The subject of illusion has been at the core of Jim’s work from the get-go. So when he serendipitously met some guy one night who was toying with a bent hanger, insisting Jim entertain him by seeing if he could visually make the wire cube turn inside out, Jim was captivated. Moving from side to side, as instructed, Jim experienced the cube floating on an invisible axis. He went rampant. Up until then, his work had implied illusion rather than created actual illusion. A chance encounter and his discovery of the Necker cube propelled him into what would become the basis of his life’s work. Like when one learns to open one’s eyes underwater for the first time, everything becomes wildly different, just knowing there is a whole other way of seeing.
Jim’s work is purely non-objective and formal, yet equally laden with profound conceptual significance. It invites an approach that is lucid and straightforward, while encouraging a willingness to let the focus blur. To hold these views simultaneously. To see and then hyper-see and be willing to not see, and in not seeing, see even more. [excerpt]https://cupola.gettysburg.edu/artcatalogs/1003/thumbnail.jp
Unfolding simulations reveal the mechanism of extreme unfolding cooperativity in the kinetically stable alpha-lytic protease.
Kinetically stable proteins, those whose stability is derived from their slow unfolding kinetics and not thermodynamics, are examples of evolution's best attempts at suppressing unfolding. Especially in highly proteolytic environments, both partially and fully unfolded proteins face potential inactivation through degradation and/or aggregation, hence, slowing unfolding can greatly extend a protein's functional lifetime. The prokaryotic serine protease alpha-lytic protease (alphaLP) has done just that, as its unfolding is both very slow (t(1/2) approximately 1 year) and so cooperative that partial unfolding is negligible, providing a functional advantage over its thermodynamically stable homologs, such as trypsin. Previous studies have identified regions of the domain interface as critical to alphaLP unfolding, though a complete description of the unfolding pathway is missing. In order to identify the alphaLP unfolding pathway and the mechanism for its extreme cooperativity, we performed high temperature molecular dynamics unfolding simulations of both alphaLP and trypsin. The simulated alphaLP unfolding pathway produces a robust transition state ensemble consistent with prior biochemical experiments and clearly shows that unfolding proceeds through a preferential disruption of the domain interface. Through a novel method of calculating unfolding cooperativity, we show that alphaLP unfolds extremely cooperatively while trypsin unfolds gradually. Finally, by examining the behavior of both domain interfaces, we propose a model for the differential unfolding cooperativity of alphaLP and trypsin involving three key regions that differ between the kinetically stable and thermodynamically stable classes of serine proteases
Les Studien über die Deutschen : un correctif à la théorie du processus de civilisation ?
Dans les Studien über die Deutschen, Norbert Elias renvoie à son livre de 1939 sur le processus de civilisation. Mais les Studien ont un autre objet (l'histoire allemande, la ‘décivilisation‘) et ont été publiées dans un tout autre contexte. Sans remettre en cause les principes fondamentaux de sa théorie, Elias l'infléchit sur trois points : 1. Il insiste sur l'humanisation de l'autocontrôle. 2. Il met en évidence le caractère précaire de la civilisation et introduit le concept de décivilisation 3. Tout en mettant en œuvre sa sociologie des figurations, il l'adapte à la complexité du matériau historique
Dissecting apoptosis the omics way
A combined analysis of transcription, translation and protein degradation reveals the global effects of an anticancer drug on tumour cells
Paper-Based Microfluidic Devices For Forensic Sciences: Development And Validation Of Innovative Tools
Laboratory analyses usually require sophisticated equipment and skilled personnel. However, very often, the use of simplified procedures and techniques in various working conditions can prove useful in solving several problems. Forensic applications represent an emblematic example of this requirement to simplify and solve various difficulties. Legal medicine requires both highly sophisticated techniques to solve analytical problems and simple techniques with fast procedures that allow analyses to be carried out outside the laboratory, in remote areas by unqualified personnel. The implementation of paper-based microfluidic analytical devices (PADs) for legal medicine presents an opportunity to tackle all the aforementioned limitations and requirements in the field of forensic science. It is also important to note that little to no sample preparation is required, with the ability to use many samples directly onto the PADs for the analysis of the desired analyte. PADs are very inexpensive to produce and ca
A Study of the Influence of the Restorative Justice Model on Out-of-School Suspensions in a Large School District
The purpose of this quantitative study was to investigate whether the Restorative Justice model influenced the number of days that students were suspended out-of-school or the number of out-of-school suspension incidents. In addition, the researcher analyzed whether the Restorative Justice model had different impacts for the subgroups of students qualifying for free and reduced lunch (FRL), English Learners (EL), students qualifying for exceptional student education services (ESE), and three ethnic subgroups (White, Black, and Hispanic) in an urban school district in Central Florida for the sixth-, seventh-, and eighth-grade students for the seven school years from 2010-2011 to 2016-2017. Primary data analysis strategies were descriptive statistics and visual analyses utilizing an interrupted time series design. The findings can be helpful in informing decision makers if the Restorative Justice model is having a positive influence on decreasing out-of-school suspension incidents and/or out-of-school suspension days
Civilian Aviation Screening: A Time-Series Analysis of Confiscated Firearms at Screening Checkpoints
This study investigated the aviation screening process and sought to determine if the federalization of the screening process had any effect on the number of firearm confiscations at civilian aviation screening checkpoints. The hypothesis of the study was that airport screening firearms confiscations (per one million screenings) were lower before the U.S. government (TSA) took over screening in 2001-2002. This quantitative research required the performance of an interrupted time series analysis. Interrupted time series analysis evaluates the impact of one or more events on the values in the time series. An interrupted time series analysis attempts to determine whether an outside event affected subsequent observations. For an example, did the implementation of a new economic policy improve economic performance, did a new gun ordinance reduce violent crimes; or in this study, did the federalization of civilian airport screening increase the number of confiscated firearms. Such comparison of an interrupted time series was applied to this study of firearm confiscations at airport checkpoints.
Due to limited publically available data and inconsistencies in data collection, firearms were the only category of confiscations available that provided sufficient data points (years of data) to conduct quantitative research. The first data set includes persons screened and firearms confiscated from years 1990 through 2000. The second set of data includes persons screened and firearms confiscated from years 2003 through 2009. The total data that was used spans a twenty year period (1990-2009). An examination the theoretical screening process model used by the private sector and the process model currently in use by the Transportation Security Administration (TSA) was performed to determine if any technological advances or changes in screening process may have had an effect on the statistical results.
The results of the investigation revealed the following findings:
1. There was no statistically significant difference between the number of firearm confiscations by private screeners and the number of firearms confiscated by government screeners.
2. Advancements in screening technology had little to no effect on the number of confiscated firearms between both theoretical process models
Uganda\u27s Agard Didi Views on Rwanda Conflict
Didi talks of strong anti-RPF, Tutsi, and Uganda propaganda that has brainwashed the population of Rwanda. Believes this propaganda will make the war unwinnable for the RPF.https://digitalcommons.georgefox.edu/rawson_rwanda/1197/thumbnail.jp
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