Throughout much of human history, the vast majority of people lived in small communities. However, in the last few centuries, and particularly in recent decades, there has been a dramatic shift. A ...massive migration has moved populations from rural to urban areas. United Nations reports state that over 4.3 billion individuals now inhabit urban regions, which accounts for more than half (55% as of 2017) of the global population. In most high-income nations, including Western Europe, the Americas, Australia, Japan, and the Middle East, over 80% of people live in urban areas. This figure ranges from 50% to 80% in upper-middle-income countries like Eastern Europe, East Asia, North Africa, South Africa, and South America (United Nations, Department of Economic and Social Affairs, Population Division, 2019). The urban population is anticipated to rise across all countries in the coming decades, albeit at different rates. By 2050, the global population is expected to reach approximately 9.8 billion, with about 6.7 billion residing in cities and 3.1 billion in rural areas. Despite this rapid urbanization, only around 1% of the Earth's land is allocated for urban and infrastructure development. While urbanization has spurred socio-economic growth, it has also led to significant challenges such as traffic congestion and air pollution. In China, the swift growth of cities has notably expanded urban areas and extended the commuting times of residents. The “2022 Commuting Monitoring Report of Major Chinese Cities” reveals that in 2022, over 14 million people in 44 major Chinese cities experienced extreme commuting, with upwards of 13% spending over an hour in transit (Baidu Maps, 2023). Beijing recorded the highest rate, where 26% of commuters faced this issue.
Copper is required for the activity of cytochrome c oxidase (COX), the terminal electron-accepting complex of the mitochondrial respiratory chain. The likely source of copper used for COX biogenesis ...is a labile pool found in the mitochondrial matrix. In mammals, the proteins that transport copper across the inner mitochondrial membrane remain unknown. We previously reported that the mitochondrial carrier family protein Pic2 in budding yeast is a copper importer. The closest Pic2 ortholog in mammalian cells is the mitochondrial phosphate carrier SLC25A3. Here, to investigate whether SLC25A3 also transports copper, we manipulated its expression in several murine and human cell lines. SLC25A3 knockdown or deletion consistently resulted in an isolated COX deficiency in these cells, and copper addition to the culture medium suppressed these biochemical defects. Consistent with a conserved role for SLC25A3 in copper transport, its heterologous expression in yeast complemented copper-specific defects observed upon deletion of PIC2. Additionally, assays in Lactococcus lactis and in reconstituted liposomes directly demonstrated that SLC25A3 functions as a copper transporter. Taken together, these data indicate that SLC25A3 can transport copper both in vitro and in vivo.
A ubiquitous feature of neurotransmitter transporters is the presence of short C-terminal PDZ binding motifs acting as important trafficking elements. Depending on their very C-terminal sequences, ...PDZ binding motifs are usually divided into at least three groups; however this classification has recently been questioned. To introduce a 3D aspect into transporter's PDZ motif similarities, we compared their interactions with the natural collection of all 13 PDZ domains of the largest PDZ binding protein MUPP1. The GABA, glycine and serotonin transporters showed unique binding preferences scattered over one or several MUPP1 domains. On the contrary, the dopamine and norepinephrine transporter PDZ motifs did not show any significant affinity to MUPP1 domains. Interestingly, despite their terminal sequence diversity all three GABA transporter PDZ motifs interacted with MUPP1 domain 7. These results indicate that similarities in binding schemes of individual transporter groups might exist. Results also suggest the existence of variable PDZ binding modes, allowing several transporters to interact with identical PDZ domains and potentially share interaction partners in vivo.
This paper examines governance responses to Mobility as a Service (MaaS). The analysis focuses on the interactions between public transport systems and MaaS developments in Amsterdam, Birmingham, and ...Helsinki. Case comparison is informed by the multilevel perspective on socio-technical transitions and literature on meta-governance of networks. Drawing on these frameworks and empirical findings, the paper identifies six governance approaches to MaaS across cases: analyser, architect, convener, experimenter, lawmaker, and provider. These basic models encompass strategies ranging from hands-on strong intervention to information collection efforts. Consistent with the transitions literature, these six approaches indicate that public transport regimes seek to control the apparent disruptive potential of MaaS by incrementally absorbing innovations; to this end, regime actors adopt governance responses that tend to reproduce existing institutionalised ways of doing and prevailing logics. Furthermore, the six approaches reveal intense interaction between regime and niche, suggesting that a niche-regime space might have emerged in the cases; actors travel and operate across niche, regime, and niche-regimes, mainly driven by concerns with market share and revenue streams in the mobility system.
Pyruvate constitutes a critical branch point in cellular carbon metabolism. We have identified two proteins, Mpc1 and Mpc2, as essential for mitochondrial pyruvate transport in yeast Drosophila, and ...humans. Mpc1 and Mpc2 associate to form an ~150-kilodalton complex in the inner mitochondrial membrane. Yeast and Drosophila mutants lacking MPC1 display impaired pyruvate metabolism, with an accumulation of upstream metabolites and a depletion of tricarboxylic acid cycle intermediates. Loss of yeast Mpc1 results in defective mitochondrial pyruvate uptake, and silencing of MPC1 or MPC2 in mammalian cells impairs pyruvate oxidation. A point mutation in MPC1 provides resistance to a known inhibitor of the mitochondrial pyruvate carrier. Human genetic studies of three families with children suffering from lactic acidosis and hyperpyruvatemia revealed a causal locus that mapped to MPC1, changing single amino acids that are conserved throughout eukaryotes. These data demonstrate that Mpc1 and Mpc2 form an essential part of the mitochondrial pyruvate carrier.
Border Management Modernization Gerard McLinden, Enrique Fanta, David Widdowson, Tom Doyle
2011, 2010, 11-30-2010, 20110101
eBook, Book
Odprti dostop
This book provides border management policymakers and reformers with a broad survey of key developments in and principles for improving trade facilitation through better border management, including ...practical advice on particular issues. In contrast to the traditional border management reform agenda, with its focus on improving customs operations, this book addresses both customs reform and areas well beyond customs-a significant broadening of scope. The book thus presents a new, more comprehensive approach to trade facilitation through border management reform: an approach that embraces a much wider, 'whole of government' perspective. The objective of this book is to summarize and provide guidance on what constitutes good practices in border management- looking beyond customs clearance. The contributions to the volume make clear that there are no simple or universally applicable solutions. Instead, the aim is to provide a range of general guidelines that can be used to better understand the complex border management environment and the interdependencies and interrelationships that collectively need to be addressed to secure meaningful change and improvement.
Expansion of the APC superfamily of secondary carriers Vastermark, Ake; Wollwage, Simon; Houle, Michael E. ...
Proteins, structure, function, and bioinformatics,
October 2014, Letnik:
82, Številka:
10
Journal Article
Solute carriers (SLCs) are the largest family of transmembrane transporters in humans and are major determinants of cellular metabolism. Several SLCs have been shown to be required for the uptake of ...chemical compounds into cellular systems, but systematic surveys of transporter-drug relationships in human cells are currently lacking. We performed a series of genetic screens in a haploid human cell line against 60 cytotoxic compounds representative of the chemical space populated by approved drugs. By using an SLC-focused CRISPR-Cas9 library, we identified transporters whose absence induced resistance to the drugs tested. This included dependencies involving the transporters SLC11A2/SLC16A1 for artemisinin derivatives and SLC35A2/SLC38A5 for cisplatin. The functional dependence on SLCs observed for a significant proportion of the screened compounds suggests a widespread role for SLCs in the uptake and cellular activity of cytotoxic drugs and provides an experimentally validated set of SLC-drug associations for a number of clinically relevant compounds.
This book aims to help the policymaker and development community in general to understand the nature of the problems and policy dilemmas that landlocked countries face to trade with the rest of the ...World. This volume presents an important breakthrough in the literature, by focusing on a new conceptual framework that challenges the previous paradigm based on physical infrastructure and state-led access solutions, embodied in many treaties. By recognizing that the main access problems for landlocked countries occur in the territory of the transit country, this volume provides a new approach to understand the set of incentives that drive the political economy and shape the institutions governing goods? transit along corridors. Overall, the policy levers available to overcome these barriers are based on universally applied principles, recognizing the need for re-engineering current transit regimes which have been implemented with little success outside Europe. A risk-approach to border control and technology use, along with trust building between private operators and public agencies, all point toward the need to encourage and formally recognize higher-quality trucking companies. Meanwhile, other modes of transportation represent an alternative to road transit, but they also entail disadvantages, suggesting that their role is likely to remain limited to niche segments, specific commodities and exceptional market circumstances.
Mitochondrial Ca(2+) (Ca(2+)(m)) uptake is mediated by an inner membrane Ca(2+) channel called the uniporter. Ca(2+) uptake is driven by the considerable voltage present across the inner membrane ...(ΔΨ(m)) generated by proton pumping by the respiratory chain. Mitochondrial matrix Ca(2+) concentration is maintained five to six orders of magnitude lower than its equilibrium level, but the molecular mechanisms for how this is achieved are not clear. Here, we demonstrate that the mitochondrial protein MICU1 is required to preserve normal Ca(2+)(m) under basal conditions. In its absence, mitochondria become constitutively loaded with Ca(2+), triggering excessive reactive oxygen species generation and sensitivity to apoptotic stress. MICU1 interacts with the uniporter pore-forming subunit MCU and sets a Ca(2+) threshold for Ca(2+)(m) uptake without affecting the kinetic properties of MCU-mediated Ca(2+) uptake. Thus, MICU1 is a gatekeeper of MCU-mediated Ca(2+)(m) uptake that is essential to prevent Ca(2+)(m) overload and associated stress.
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