The organic anion transporters (OATs) and organic anion–transporting polypeptides (OATPs) belong to the solute carrier (SLC) transporter superfamily and play important roles in handling various endogenous and exogenous compounds of anionic charge. The OATs and OATPs are often implicated in drug therapy by impacting the pharmacokinetics of clinically important drugs and, thereby, drug exposure in the target organs or cells. Various mechanisms (e.g. genetic, environmental, and disease-related factors, drug-drug interactions, and food-drug interactions) can lead to variations in the expression and activity of the anion drug-transporting proteins of OATs and OATPs, possibly impacting the therapeutic outcomes. Previous investigations mainly focused on the regulation at the transcriptional level and drug-drug interactions as competing substrates or inhibitors. Recently, evidence has accumulated that cellular trafficking, post-translational modification, and degradation mechanisms serve as another important layer for the mechanisms underlying the variations in the OATs and OATPs. This review will provide a brief overview of the major OATs and OATPs implicated in drug therapy and summarize recent progress in our understanding of the post-translational modifications, in particular ubiquitination and degradation pathways of the individual OATs and OATPs implicated in drug therapy.

The plasma membrane of a cell is characterized by an asymmetric distribution of lipid species across the exofacial and cytofacial aspects of the bilayer. Regulation of membrane asymmetry is a fundamental characteristic of membrane biology and is crucial for signal transduction, vesicle transport, and cell division. The type IV family of P-ATPases, or P4-ATPases, establishes membrane asymmetry by selection and transfer of a subset of membrane lipids from the lumenal or exofacial leaflet to the cytofacial aspect of the bilayer. It is unclear how P4-ATPases sort through the spectrum of membrane lipids to identify their desired substrate(s) and how the membrane environment modulates this activity. Therefore, we tested how the yeast plasma membrane P4-ATPase, Dnf2, responds to changes in membrane composition induced by perturbation of endogenous lipid biosynthetic pathways or exogenous application of lipid. The primary substrates of Dnf2 are glucosylceramide (GlcCer) and phosphatidylcholine (PC, or their lyso-lipid derivatives), and we find that these substrates compete with each other for transport. Acutely inhibiting sphingolipid synthesis using myriocin attenuates transport of exogenously applied GlcCer without perturbing PC transport. Deletion of genes controlling later steps of glycosphingolipid production also perturb GlcCer transport to a greater extent than PC transport. In contrast, perturbation of ergosterol biosynthesis reduces PC and GlcCer transport equivalently. Surprisingly, application of lipids that are poor transport substrates differentially affects PC and GlcCer transport by Dnf2, thus altering substrate preference. Our data indicate that Dnf2 exhibits exquisite sensitivity to the membrane composition, thus providing feedback onto the function of the P4-ATPases.

Kir2.1, a strong inward rectifier potassium channel encoded by the KCNJ2 gene, is a key regulator of the resting membrane potential of the cardiomyocyte and plays an important role in controlling ventricular excitation and action potential duration in the human heart. Mutations in KCNJ2 result in inheritable cardiac diseases in humans, e.g. the type-1 Andersen-Tawil syndrome (ATS1). Understanding the molecular mechanisms that govern the regulation of inward rectifier potassium currents by Kir2.1 in both normal and disease contexts should help uncover novel targets for therapeutic intervention in ATS1 and other Kir2.1-associated channelopathies. The information available to date on protein-protein interactions involving Kir2.1 channels remains limited. Additional efforts are necessary to provide a comprehensive map of the Kir2.1 interactome. Here we describe the generation of a comprehensive map of the Kir2.1 interactome using the proximity-labeling approach BioID. Most of the 218 high-confidence Kir2.1 channel interactions we identified are novel and encompass various molecular mechanisms of Kir2.1 function, ranging from intracellular trafficking to cross-talk with the insulin-like growth factor receptor signaling pathway, as well as lysosomal degradation. Our map also explores the variations in the interactome profiles of Kir2.1^WT versus Kir2.1^314-315, a trafficking deficient ATS1 mutant, thus uncovering molecular mechanisms whose malfunctions may underlie ATS1 disease. Finally, using patch-clamp analysis, we validate the functional relevance of PKP4, one of our top BioID interactors, to the modulation of Kir2.1-controlled inward rectifier potassium currents. Our results validate the power of our BioID approach in identifying functionally relevant Kir2.1 interactors and underline the value of our Kir2.1 interactome as a repository for numerous novel biological hypotheses on Kir2.1 and Kir2.1-associated diseases.

The Discoidin, CUB, and LCCL domain-containing protein (DCBLD) family consists of two type-I transmembrane scaffolding receptors, DCBLD1 and DCBLD2, which play important roles in development and cancer. The nonreceptor tyrosine kinases FYN and ABL are known to drive phosphorylation of tyrosine residues in YXXP motifs within the intracellular domains of DCBLD family members, which leads to the recruitment of the Src homology 2 (SH2) domain of the adaptors CT10 regulator of kinase (CRK) and CRK-like (CRKL). We previously characterized the FYN- and ABL-driven phosphorylation of DCBLD family YXXP motifs. However, we have identified additional FYN- and ABL-dependent phosphorylation sites on DCBLD1 and DCBLD2. This suggests that beyond CRK and CRKL, additional DCBLD interactors may be regulated by FYN and ABL activity. Here, we report a quantitative proteomics approach in which we map the FYN- and ABL-regulated interactomes of DCBLD family members. We found FYN and ABL regulated the binding of several signaling molecules to DCBLD1 and DCBLD2, including members of the 14-3-3 family of adaptors. Biochemical investigation of the DCBLD2/14-3-3 interaction revealed ABL-induced binding of 14-3-3 family members directly to DCBLD2.

Small admixtures in water, e.g. of metal ions, often act as cell growth regulators. Here we report that enrichment of deuterium content in water, normally found at 8 mm concentration, two-three folds increases cell proliferation and lowers the oxidative stress level as well. Acting as an anti-oxidant, deuterium-enriched water prevents the toxic effect of such oxidative agents as hydrogen peroxide and auranofin. This action is opposite to that of deuterium depletion that is known to suppress cell growth and induce oxidative stress in mitochondria. We thus hypothesize that deuterium may be a natural cell growth regulator that controls mitochondrial oxidation-reduction balance. Because growth acceleration is reduced approximately by half by addition to water a minute amount (0.15%) of ¹⁸O isotope, at least part of the deuterium effect on cell growth can be explained by the isotopic resonance phenomenon. A slight (2-fold) enrichment of deuterium in water accelerates human cell growth. Quantitative MS based proteomics determined changes in protein abundances and redox states and found that deuterium-enriched water acts mainly through decreasing ROS production in mitochondria. This action is opposite to that of deuterium depletion that suppresses cell growth by inducing oxidative stress. Thus deuterium may be a natural cell growth regulator that controls mitochondrial oxidation-reduction balance. The role of isotopic resonance in this effect was validated by further experiments on bacteria.

Mallory-Denk-bodies (MDBs) are hepatic protein aggregates associated with inflammation both clinically and in MDB-inducing models. Similar protein aggregation in neurodegenerative diseases also triggers inflammation and NF-B activation. However, the precise mechanism that links protein aggregation to NF-B-activation and inflammatory response remains unclear. Herein we find that treating primary hepatocytes with MDB-inducing agents (N-methylprotoporphyrin (NMPP), protoporphyrin IX (PPIX), or Zinc-protoporphyrin IX (ZnPP)) elicited an IBα-loss with consequent NF-B activation. Four known mechanisms of IBα-loss i.e. the canonical ubiquitin-dependent proteasomal degradation (UPD), autophagic-lysosomal degradation, calpain degradation and translational inhibition, were all probed and excluded. Immunofluorescence analyses of ZnPP-treated cells coupled with 8 M urea/CHAPS-extraction revealed that this IBα-loss was due to its sequestration along with IBβ into insoluble aggregates, thereby releasing NF-B. Through affinity pulldown, proximity biotinylation by antibody recognition, and other proteomic analyses, we verified that NF-B subunit p65, which stably interacts with IBα under normal conditions, no longer binds to it upon ZnPP-treatment. Additionally, we identified 10 proteins that interact with IBα under baseline conditions, aggregate upon ZnPP-treatment, and maintain the interaction with IBα after ZnPP-treatment, either by cosequestering into insoluble aggregates or through a different mechanism. Of these 10 proteins, the nucleoporins Nup153 and Nup358/RanBP2 were identified through RNA-interference, as mediators of IBα-nuclear import. The concurrent aggregation of IBα, NUP153, and RanBP2 upon ZnPP-treatment, synergistically precluded the nuclear entry of IBα and its consequent binding and termination of NF-B activation. This novel mechanism may account for the protein aggregate-induced inflammation observed in liver diseases, thus identifying novel targets for therapeutic intervention. Because of inherent commonalities this MDB cell model is a bona fide protoporphyric model, making these findings equally relevant to the liver inflammation associated with clinical protoporphyria.

Oxidative stress has been implicated in aging and many human diseases, notably neurodegenerative disorders and various cancers. The reactive oxygen species that are generated by aerobic metabolism and environmental stressors can chemically modify proteins and alter their biological functions. Cells possess protein repair pathways to rescue oxidized proteins and restore their functions. If these repair processes fail, oxidized proteins may become cytotoxic. Cell homeostasis and viability are therefore dependent on the removal of oxidatively damaged proteins. Numerous studies have demonstrated that the proteasome plays a pivotal role in the selective recognition and degradation of oxidized proteins. Despite extensive research, oxidative stress-triggered regulation of proteasome complexes remains poorly defined. Better understanding of molecular mechanisms underlying proteasome function in response to oxidative stress will provide a basis for developing new strategies aimed at improving cell viability and recovery as well as attenuating oxidation-induced cytotoxicity associated with aging and disease. Here we highlight recent advances in the understanding of proteasome structure and function during oxidative stress and describe how cells cope with oxidative stress through proteasome-dependent degradation pathways.

China's Regions in an Era of Globalization Book sysadmin 14 May 2018

The rise of China has been shaped and driven by its engagement with the global economy. This engagement cannot be understood at the level of national policymaking alone, but requires analysis of the differences in participation in the global economy across China’s regions.

China is a continent-sized economy and society with substantial diversity across its different regions. This book traces the evolution of regional policy in China and its implications in a global context.

Detailed chapters examine the trajectory of what is now becoming known as the Greater Bay Area in southern China, the inland mega-city of Chongqing, and the role of China’s regions in the globally focused Belt and Road Initiative launched by the Chinese government in late 2013.

It will be of interest to practitioners and scholars engaging with contemporary China’s political economy and international relations.

This book is published as part of the Insights series.

Praise for China’s Regions in an Era of Globalization

About the author

Tim Summers works on the political economy and international relations of contemporary China. He is a Lecturer at the Centre for China Studies, The Chinese University of Hong Kong, and a (non-resident) Senior Consulting Fellow on the Asia-Pacific Programme at Chatham House. He was British consul general in Chongqing from 2004 to 2007.

This book is published in collaboration with Routledge.

Purchase

• Worldwide (via Routledge)
• Students (via Browns Books)

VOLUME 279 (2004) PAGES 33438–33446For Fig. 1B, the second, third, and fifth panels were mistakenly duplicated during article preparation as no yeast colonies were observed in these conditions. The corrected images are presented in the revised Fig. 1B. This correction does not affect the results or conclusions of the work. The authors apologize for the error.jbc;295/50/17382/F1F1F1Figure 1B.

Zimbabwe’s Economic Governance and Regional Integration 17 November 2020 — 12:00PM TO 1:30PM Anonymous (not verified) 6 November 2020 Online

Panellists discuss policy and governance for long-term economic prosperity in Zimbabwe, reflecting on the role of institutional change and regional integration in the context of the shocks caused by the coronavirus pandemic.

At this virtual event, panellists and participants will discuss policy and governance for long-term economic prosperity in Zimbabwe, reflecting on the role of institutional change and regional integration.

The government of Zimbabwe has emphasized its commitment to economic reform and its ambition to achieve upper-middle-income status by 2030, but there are considerable challenges to overcome.

The COVID-19 pandemic has exacerbated existing economic fragility. Improving the business climate to attract international private-sector investment will be contingent on clear, consistent and coherent policy and implementation, including targeting abuse and corruption.

Zimbabwe has, in recent years, successfully strengthened its regional trade integration, although some trade frictions remain. This is an important factor not only for catalysing economic growth in Zimbabwe, but for supporting regional prosperity and post-COVID recovery.

This webinar is the second in a series of events held in partnership with the Konrad Adenauer Stiftung on Zimbabwe’s economic reform and recovery.

Read a meeting summary

This event will also be broadcast live on the Africa Programme Facebook page.

The era of ‘reglobalization’ 15 June 2023 — 6:00PM TO 7:00PM Anonymous (not verified) 14 February 2023 Chatham House and Online

How to balance international trade with efforts to enhance domestic economic resilience?

The global trade outlook remains challenging in 2023. Geopolitical tensions and national security concerns are playing a greater role in trade policy with a focus on strengthening supply chain resilience and reducing economic dependencies. In addition, the turn towards industrial policies has raised concerns about unfair trade practices and protectionism.

The debate about the future of globalization has only therefore deepened. While ‘deglobalization’ dominates the current public discourse on trade, is ‘reglobalization’ a better term to describe patterns of economic integration and fracturing across different economies and sectors?

The panel of experts discuss:

• To what extent are efforts to meet climate goals and maintain technological leadership intertwined with industrial policy and national security objectives?

• What do recent measures by the US – including the Inflation Reduction Act and a push on semiconductors – mean for cooperation with like-minded partners such as the EU?

• Are any countries resisting the protectionist trend and continuing to champion open trade?

• What steps can be taken to strengthen strategic and sensitive supply chains, for example, for critical minerals, high-capacity batteries and semiconductors?

• Is it possible to develop and advance a positive trade agenda for a reglobalized world? If so, what would it look like?

As with all member events, questions from the audience drive the conversation.

Russia's war: How will it shape the region's future? 1 December 2022 — 9:00AM TO 6:00PM Anonymous (not verified) 17 August 2022 Chatham House and Online

This conference takes a deep-dive into the implications of the war for the wider region.

You will receive an email in advance of the conference with further details on accessing the event.

The video on this page is of the opening session only. To view all the session videos, please visit the conference playlist on YouTube.

How will Russia’s war shape the region’s future?

Russia’s latest invasion of Ukraine is on such a scale that it will have a seismic effect on all the countries that once formed the Soviet empire. Vladimir Putin’s decisions have accelerated trends across the region leading to unintended consequences.

Now it is more crucial than ever – not only for those concerned with the region’s economic and democratic development, but for all those with a stake in the future security of Europe.

For some states, this will mean a faster break from the legacy of the USSR and from Russia’s ‘Geopathological embrace‘ while, for others, maybe even a fresh start at democracy and good governance.

In isolated cases, the war will conceivably hasten assimilation with Russia. But the two principal combatants, Ukraine and Russia, will diverge even further. Ukraine, though fighting for its survival now, will at least get the opportunity to ‘build back better’ if it achieves some form of victory.

Whatever the course of the war, however, Russia’s aspirations to be a global power again are doomed as it is gradually deglobalized from Western structures.

This conference analyses:

• How Russia’s war will affect the broader regional economy and whether this will hasten Vladimir Putin’s exit
• What to hope for, what to fear and the key trends that will dominate the region going forward.
• Unique expertise in an independent forum on what’s at stake for Europe. 

Tesla Friday reached a $1 trillion market capitalization value for the first time since 2022 in a post-election stock rally.

A flight of Florida-based Spirit Airlines was hit by gunfire while attempting to land in Haiti with a crew member that sustained "minor injuries."

Oregon, Ohio State, Georgia and Miami lead the first edition of the 2024-25 College Football Playoff rankings, the selection committee announced.

A boom in AI has created a problem for the organizers of the NeurIPS conference, which is considered an essential machine-learning research conference. The sheer number of registrations has overwhelmed […]

The post Lottery to Determine Major AI Conference Attendees Amid Registration Boom appeared first on HPCwire.

On Nov. 13, 1956, the U.S. Supreme Court upheld the federal district court's ruling in Browder v. Gayle (1956) that segregation on interstate buses was unconstitutional.

NASA has identified nine possible landing sites for its Artemis III mission in September 2026 that will return astronauts to the moon for the first time in more than 50 years, the space agency announced Monday.

In this ode to improvisation, musician and comedian Reggie Watts beatboxes, raps, loops his own rhythms and reflects upon the everyday power of turning the mundane into magic. After all, he says, we're all just making it up as we go along.

Over his decades of farming and ranching, Gabe Brown has noticed a troubling trend: the conventional farming techniques he used were degrading the soil and harming nature. He shares how his family farm turned things around by adopting regenerative agricultural practices — and shows how the wider food system can use these same methods to improve food quality and revitalize the land.

State of the States: Education highlights from latest governor's address before the legislature.

Oregon is building on several efforts to improve how schools use technology, relying on local and federal money for support.

New report on Oregon's tribal students show they start out behind, miss more school, and are more likely to drop out.

Matthew Utterback, the superintendent of the North Clackamas district in Oregon, was named last week as the 2017 National Superintendent of the Year.

Gov. Kulongoski’s State of the State speech called broadly for more investment in Oregon’s education system, from preschool to graduate school, but included no specific dollar figures for K-12 schools.

Oregon is the latest state to consider adding an ethnic studies curriculum.

Gov. Kate Brown ordered the public release of annual school performance ratings last week after Oregon's biggest newspaper reported that a Brown appointee had delayed the release of the statistical rankings until after the high-stakes gubernatorial election Nov. 6.

Three Oregon school employees sued their union in federal court last week, arguing it's unfair that the teachers' union only lets members drop out and stop paying dues during the month of September.

This Quality Counts 2019 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

A federal appeals court rejected a multi-pronged challenge to a school district plan allowing transgender students to use restrooms and other facilities that match their gender identity.

This Quality Counts 2020 Highlights Report captures all the data you need to assess your state's performance on key educational outcomes.

When schools reduce racial segregation between schools, racial isolation within the classes inside those schools goes up, according to an analysis of 20 years of North Carolina data.

Court-ordered school desegregation has been more successful in the South than in any other region of the country, but researchers have noted a new threat: the growing number of communities that are seceding from larger school districts to form their own.

Dougherty County, a largely black school district in an region heavily affected by coronavirus, is no longer subject to desegregation orders first imposed in 1963.

Nothing has changed at the top of the second 2024 College Football Playoff rankings.

The second College Football Playoff rankings were released, with the big questions surrounding who would be No. 3 and where the SEC teams would land.

No. 1 Oregon will travel to Madison this weekend to take on the Wisconsin Badgers at Camp Randall Stadium.

Penn State is on the verge of doing something that it hasn’t done in more than 40 years. The Nittany Lions can post three straight straight 10-win seasons for the first time since 1980-82 with its next two victories. It would be their sixth season with double-digit wins in nine years, the best such stretch since the program’s golden era from 1977-86. Yet some in the sellout crowd of 110,233 at ...

The Big Ten captured four of the top five spots led by Oregon and Ohio State.

It's Oregon women's basketball vs. Baylor in a marquee nonconference college basketball matchup. Follow for live score updates, game highlights.

South Carolina a unanimous No. in women's AP Top 25 after 2 wins to open repeat bid; Stanford, Oregon crack rankings.

The Gamecocks earned a hard-fought six-point win over Michigan in Las Vegas to open the season and beat then-No. 9 North Carolina State on Sunday by 14. The two victories made the defending champions a unanimous choice from the 31-member national media panel. In the preseason poll, No. 2 UConn got two first-place votes and No. 3 USC one.

Elisa Mevius and Nani Falatea each scored 11 points and No. 25 Oregon routed North Texas 66-35 on Tuesday for its fourth straight victory. Mevius scored the final four points of the first quarter to give Oregon a 14-4 lead as North Texas was just 2 of 11 from the field. Falatea made the first field goal of the second quarter for a 17-6 lead and the Ducks led by double figures the rest of the way.

Holly Oakley
Oct 4, 2006; 26:10129-10140
Neurobiology of Disease