Protein-tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed PTP that is anchored to the endoplasmic reticulum (ER). PTP1B dephosphorylates activated receptor tyrosine kinases after ...endocytosis, as they transit past the ER. However, PTP1B also can access some plasma membrane (PM)-bound substrates at points of cell-cell contact. To explore how PTP1B interacts with such substrates, we utilized quantitative cellular imaging approaches and mathematical modeling of protein mobility. We find that the ER network comes in close proximity to the PM at apparently specialized regions of cell-cell contact, enabling PTP1B to engage substrate(s) at these sites. Studies using PTP1B mutants show that the ER anchor plays an important role in restricting its interactions with PM substrates mainly to regions of cell-cell contact. In addition, treatment with PTP1B inhibitor leads to increased tyrosine phosphorylation of EphA2, a PTP1B substrate, specifically at regions of cell-cell contact. Collectively, our results identify PM-proximal sub-regions of the ER as important sites of cellular signaling regulation by PTP1B.
Lipidated Rho and Rab GTP-binding proteins are transported between membranes in complex with solubilizing factors called 'guanine nucleotide dissociation inhibitors' (GDIs). Unloading from GDIs using ...GDI displacement factors (GDFs) has been proposed but remains mechanistically elusive. PDEδ is a putative solubilizing factor for several prenylated Ras-subfamily proteins. Here we report the structure of fully modified farnesylated Rheb-GDP in complex with PDEδ. The structure explains the nucleotide-independent binding of Rheb to PDEδ and the relaxed specificity of PDEδ. We demonstrate that the G proteins Arl2 and Arl3 act in a GTP-dependent manner as allosteric release factors for farnesylated cargo. We thus describe a new transport system for farnesylated G proteins involving a GDI-like molecule and an unequivocal GDF. Considering the importance of PDEδ for proper Ras and Rheb signaling, this study is instrumental in developing a new target for anticancer therapy.
Background
This study estimates the socioeconomic impact of migraine headaches on paid and unpaid work productivity in the adult German population in 1 year.
Methods
We used data on headache ...frequency (days per month) from a longitudinal population-based study. Prevalence estimates of migraine were derived from the Global Burden of Disease Collaborative Network. Demography data were derived from official statistics in 2017. Aggregate headache days in 1 year were translated to losses in paid and unpaid productive hours based on estimates of presenteeism and absenteeism along with other socioeconomic parameters. Paid hours lost were distributed across the industry sectors. In this way, an age-, gender- and industry sector-specific monetary value was calculated for paid hours lost. Unpaid hours lost were valued by assigning the unpaid activities to their nearest market substitute. In a last step, value-added multipliers derived from input-output tables were used to calculate the economic value chain effects.
Results
A total of 15.5 million persons (20 years or older) suffer from migraine in Germany. Our analysis shows that 60% of those have three or fewer headache days per month, while patients suffering chronic migraine (15+ headache days per month) account for 5.4% of the adult migraine population. Females bear 65% of the total 836 million headache days per year. The socioeconomic losses due to migraine amount to €100.4 billion (€6493 on average per patient) in one year.
Conclusion
In addition to time losses in paid work, migraine causes substantial socioeconomic losses to unpaid work activities due to its disproportionate prevalence among females. Economic value chain effects provide a novel perspective on losses beyond a patient’s time loss. Overall, the elements of socioeconomic burden provide a strong rationale that innovative migraine therapies could be of high value to society.
How can a regulatory agency with historic roots in controlling pollution implement sustainability? How does an agency organized by individual media offices for air, water, toxics, and waste develop ...an integrated systems approach to environmental protection? Aligning and integrating programs is crucial for sustained environmental protection, especially in urban areas. The role of the U.S. Environmental Protection Agency (EPA) extends beyond setting national standards for air and water, protecting against chemical discharges, and restoring contaminated lands. The agency has the potential to become a national environmental architect by promoting research and innovation targeted at urban sustainability. To develop tools for creating a truly sustainable urban environmental infrastructure, EPA must develop approaches for adapting to potential climate change impacts on urban systems. In short, EPA needs an urban environmental strategy.
The formation of an activity gradient of the small G-protein Ran around chromatin depends on the differential partitioning of the opposing enzyme activities of the Ran guanine nucleotide exchange ...factor RCC1 that resides on chromatin, and the cytoplasmic Ran GTPase activating protein RanGAP. We studied the time-dependent interaction kinetics between RCC1 and chromatin and the mobility of the Ran-RCC1 complex in living cells by fluorescence correlation spectroscopy to investigate whether binding of RCC1 to chromatin regulates the exchange activity of RCC1, and whether the stability of the RCC1-chromatin interaction is regulated during the cell cycle. We found that RCC1 mobility is dominated by two states: a highly mobile state that is trapped within chromatin, and a transiently immobilized state that is stabilized during mitosis. We show that only the immobilized state of RCC1 interacts with Ran and conclude that its guanine nucleotide exchange activity is restricted to specific sites on chromatin.
Background
Evidence suggests that early highly efficacious therapy in relapsing multiple sclerosis is superior to escalation strategies.
Objective
A cost-consequence analysis simulated different ...treatment scenarios with ofatumumab (OMB), dimethyl fumarate (DMF) and glatiramer acetate (GA): immediate OMB initiation as first treatment, early switch to OMB after 1 year on DMF/GA, late switch after 5 years or no switch.
Methods
An EDSS-based Markov model with a 10-year time horizon was applied. Cycle transitions included EDSS progression, improvement or stabilization, treatment discontinuation, relapse or death. Input data were extracted from OMB trials, a network meta-analysis, published literature, and publicly available sources.
Results
The late switch compared to the immediate OMB scenario resulted in a lower proportion of patients with EDSS 0–3 (Δ − 7.5% DMF; Δ − 10.3% GA), more relapses (Δ + 0.72 DMF; Δ + 1.23 GA) and lower employment rates (Δ − 4.0% DMF; Δ − 5.6% GA). The same applies to late versus early switches. No switch scenarios resulted in worse outcomes. Higher drug acquisition costs in the immediate OMB and early switch scenarios were almost compensated by lower costs for patient care and productivity loss.
Conclusion
Immediate OMB treatment and an early switch improves clinical and productivity outcomes while remaining almost cost neutral compared to late or no switches.
Objectives: The aim of this study was to evaluate the cost-effectiveness of the dynamic intraligamentary stabilization (DIS) technique in comparison with reconstructive surgery (ACLR) in the ...treatment of isolated anterior cruciate ligament (ACL) ruptures from the perspective of the community of insured citizens in Germany. Methods: Because of the specific decision problem at hand, namely that with DIS the procedure has to take place within 21 days after the initial trauma, a decision tree was developed. The time horizon of the model was set to 3 years. Input data was taken from official tariffs, payer data, the literature and assumptions based on expert opinion when necessary. Results: The decision tree analysis identified the DIS strategy as the superior one with 2.34 QALY versus 2.26 QALY for the ACLR branch. The higher QALY also came with higher costs of 5,398.05 € for the DIS branch versus 4,632.68 € for the ACLR branch respectively, leading to an ICER of 9,092.66 € per QALY. Results were robust after sensitivity analysis. Uncertainty was examined via probabilistic sensitivity analysis resulting in a slightly higher ICER of 9,567.13 € per QALY gained. Conclusion: The DIS technology delivers an effective treatment for the ACL rupture at a favorable incremental cost-effectiveness ratio. Electronic supplementary material: The online version of this article (doi:10.1186/s13561-017-0143-9) contains supplementary material, which is available to authorized users.
How can a regulatory agency with historic roots in controlling pollution implement sustainability? How does an agency organized by individual media offices for air, water, toxics, and waste develop ...an integrated systems approach to environmental protection? Aligning and integrating programs is crucial for sustained environmental protection, especially in urban areas. The role of the U.S. Environmental Protection Agency (EPA) extends beyond setting national standards for air and water, protecting against chemical discharges, and restoring contaminated lands. The agency has the potential to become a national environmental architect by promoting research and innovation targeted at urban sustainability. To develop tools for creating a truly sustainable urban environmental infrastructure, EPA must develop approaches for adapting to potential climate change impacts on urban systems. In short, EPA needs an urban environmental strategy.
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