Preconceitos do Brasil (Text)

This text in Portuguese and its English translation accompanies the illustrated podcast in Portuguese 'Preconceitos do Brasil' created by James Letts, a student of Spanish and Latin American Studies at the School of Languages and Area Studies, Universit

Functional and Structural Studies of the Human Voltage-Gated Proton Channel

The activity of voltage-gated cation channels underlies the action potentials that allow for neuronal signaling and muscle contraction. The canonical family of voltage-gated K+, Na+ and Ca2+ channels has been the subject of extensive electrophysiological, biophysical, genetic, biochemical and structural characterization since the 1950s. These channels all share a conserved six-transmembrane helix topology (S1-S6) in which the first four transmembrane helices (S1-S4) form the regulatory voltage-sensor domain and the last two transmembrane helices (S5 and S6) comprise the ion-conducting pore domain. It was thought that all voltage-gated cation channels shared this conserved domain architecture. However, this scheme was challenged by the discovery of the gene for the voltage-gated H+ channel. This voltage-gated cation channel has a four transmembrane helix topology that is homologous to the voltage-sensor domain of the canonical voltage-gated cation channels alone, without a separate pore domain. In this thesis, I present my work, which constitutes the first ever biochemical characterization of the human voltage-gated H+ channel (hHV1). First, I demonstrate by site-specific cross-linking that hHV1 is a dimer in the membrane and define the oligomerization interface. Then, by developing methods for the heterologous expression, purification and reconstitution of hHV1, I establish that the four transmembrane helix voltage-sensor-domain-like putative channel protein is in fact responsible for H+ conduction. Next, I present my work on the structural characterization of hHV1 by X-ray crystallography. I solved a low-resolution structure of a chimeric voltage-gated proton channel but then demonstrated that although this channel is functional in a membrane, the conformation seen in the crystal is non-native. Finally, I present my work on the analysis of hHV1 by solution state NMR in detergent micelles. This technique allowed us to define the secondary structure of the channel for the first time but full three-dimensional structural characterization was determined to be unfeasible. From these studies, I conclude that the HV channel structure is dependent on the constraints imposed by the lipid bilayer and is destabilized upon detergent solubilization. Future structural studies of HV channels will have to focus on channels imbedded within a membrane-like environment

Clarifying the supercomplex: The higher-order organization of the mitochondrial electron transport chain

The oxidative phosphorylation electron transport chain (OXPHOS-ETC) of the inner mitochondrial membrane is composed of five large protein complexes, named CI-CV. These complexes convert energy from the food we eat into ATP, a small molecule used to power a multitude of essential reactions throughout the cell. OXPHOS-ETC complexes are organized into supercomplexes (SCs) of defined stoichiometry: CI forms a supercomplex with CIII2 and CIV (SC I+III2+IV, known as the respirasome), as well as with CIII2 alone (SC I+III2). CIII2 forms a supercomplex with CIV (SC III2+IV) and CV forms dimers (CV2). Recent cryo-EM studies have revealed the structures of SC I+III2+IV and SC I+III2. Furthermore, recent work has shed light on the assembly and function of the SCs. Here we review and compare these recent studies and discuss how they have advanced our understanding of mitochondrial electron transport

‘Hoovering up the Money’? : Delivering government-funded capacity-building programmes to voluntary and community organisations

The 'ChangeUp' and FutureBuilders initiatives have provided substantial funding to support and facilitate 'capacity building' in voluntary and community organisations and so enable them to contribute to the achievement of public and social policy goals. This paper builds on findings from a study of an early 'capacity-building' programme delivered between 1998 and 2005. We explore the challenges of implementing such initiatives for voluntary sector intermediary bodies involved in delivering them and for the voluntary and community organisations intended as the main beneficiaries. We conclude with a discussion about the implications for policy implementationPeer reviewedFinal Accepted Versio

Structures of respiratory supercomplex I+III2 reveal functional and conformational crosstalk

The mitochondrial electron transport chain complexes are organized into supercomplexes (SCs) of defined stoichiometry, which have been proposed to regulate electron flux via substrate channeling. We demonstrate that CoQ trapping in the isolated SC I+III2 limits complex (C)I turnover, arguing against channeling. The SC structure, resolved at up to 3.8 Å in four distinct states, suggests that CoQ oxidation may be rate limiting because of unequal access of CoQ to the active sites of CIII2. CI shows a transition between “closed” and “open” conformations, accompanied by the striking rotation of a key transmembrane helix. Furthermore, the state of CI affects the conformational flexibility within CIII2, demonstrating crosstalk between the enzymes. CoQ was identified at only three of the four binding sites in CIII2, suggesting that interaction with CI disrupts CIII2 symmetry in a functionally relevant manner. Together, these observations indicate a more nuanced functional role for the SCs

Health of War-Affected Karen Adults 5 Years Post-Resettlement

Background: An estimated 140 000 refugees from Burma have resettled to the USA since 2009, comprising 21% of total resettlement in the USA over the last decade. Our objective was to describe patterns of longitudinal health outcomes in a cohort of Karen refugees resettled in the USA for 5 years, and to translate these findings to a primary healthcare context. Methods: The study was a retrospective cohort study focused on the analysis of the first 5 years of electronic health records of a sample of 143 Karen refugees who were initially resettled between May 2011 and May 2013. Results: Through descriptive, inferential and survival statistics, we described patterns of retention in primary care, biometric trends, condition prevalence and survival probabilities. Highest prevalence health conditions documented at any point in the 5-year period included diagnoses or symptoms associated with pain (52%); gastrointestinal disturbance (41%); metabolic disorder (41%); infectious process (34%); mental health condition (31%) and central nervous system disorder (24%). Conclusions: This study is the first retrospective longitudinal analysis of patterns of health in Karen refugees originating from Burma and resettled to the USA. Findings identified in the 5-year, the post-resettlement period provided important clinical insights into the health trajectories of war-affected populations. Burden of illness was high although results did not demonstrate the extent of trauma-associated physical health conditions reported in the literature. Indicators such as significant increases in body mass index (BMI), the overall prevalence of dyslipidaemia and others suggested that the cohort may be exhibiting an early trajectory towards the development of these conditions. Authors summarize potential protective factors experienced by the cohort that promoted aspects of health frequently challenged in forced migration

The Newport Manual on the Law of Naval Warfare

The Newport Manual on the Law of Naval Warfare is the first effort to restate the law of naval warfare as a purely lex lata exercise since 1955. It is designed to provide a practical guide for commanders and seafarers, lawyers and officials, and educators and students. In doing so, the Manual also factors in the developments in warfighting technologies in recent decades, which have significantly influenced the nature of war at sea

The CMS Integration Grid Testbed

The CMS Integration Grid Testbed (IGT) comprises USCMS Tier-1 and Tier-2 hardware at the following sites: the California Institute of Technology, Fermi National Accelerator Laboratory, the University of California at San Diego, and the University of Florida at Gainesville. The IGT runs jobs using the Globus Toolkit with a DAGMan and Condor-G front end. The virtual organization (VO) is managed using VO management scripts from the European Data Grid (EDG). Gridwide monitoring is accomplished using local tools such as Ganglia interfaced into the Globus Metadata Directory Service (MDS) and the agent based Mona Lisa. Domain specific software is packaged and installed using the Distrib ution After Release (DAR) tool of CMS, while middleware under the auspices of the Virtual Data Toolkit (VDT) is distributed using Pacman. During a continuo us two month span in Fall of 2002, over 1 million official CMS GEANT based Monte Carlo events were generated and returned to CERN for analysis while being demonstrated at SC2002. In this paper, we describe the process that led to one of the world's first continuously available, functioning grids.Comment: CHEP 2003 MOCT01

Hadoop distributed file system for the Grid

Data distribution, storage and access are essential to CPU-intensive and data-intensive high performance Grid computing. A newly emerged file system, Hadoop distributed file system (HDFS), is deployed and tested within the Open Science Grid (OSG) middleware stack. Efforts have been taken to integrate HDFS with other Grid tools to build a complete service framework for the Storage Element (SE). Scalability tests show that sustained high inter-DataNode data transfer can be achieved for the cluster fully loaded with data-processing jobs. The WAN transfer to HDFS supported by BeStMan and tuned GridFTP servers shows large scalability and robustness of the system. The hadoop client can be deployed at interactive machines to support remote data access. The ability to automatically replicate precious data is especially important for computing sites, which is demonstrated at the Large Hadron Collider (LHC) computing centers. The simplicity of operations of HDFS-based SE significantly reduces the cost of ownership of Petabyte scale data storage over alternative solutions

The U.S. CMS HL-LHC R&D Strategic Plan

The HL-LHC run is anticipated to start at the end of this decade and will pose a significant challenge for the scale of the HEP software and computing infrastructure. The mission of the U.S. CMS Software & Computing Operations Program is to develop and operate the software and computing resources necessary to process CMS data expeditiously and to enable U.S. physicists to fully participate in the physics of CMS. We have developed a strategic plan to prioritize R&D efforts to reach this goal for the HL-LHC. This plan includes four grand challenges: modernizing physics software and improving algorithms, building infrastructure for exabyte-scale datasets, transforming the scientific data analysis process and transitioning from R&D to operations. We are involved in a variety of R&D projects that fall within these grand challenges. In this talk, we will introduce our four grand challenges and outline the R&D program of the U.S. CMS Software & Computing Operations Program.Comment: CHEP2023 proceedings, to be published in EPJ Web of Conference