Secondary anionic phospholipid binding site and gating mechanism in Kir2.1 inward rectifier channels

Inwardly rectifying potassium (Kir) channels regulate multiple tissues. All Kir channels require interaction of phosphatidyl-4,5-bisphosphate (PIP(2)) at a crystallographically identified binding site, but an additional nonspecific secondary anionic phospholipid (PL(−)) is required to generate high PIP(2) sensitivity of Kir2 channel gating. The PL(−)-binding site and mechanism are yet to be elucidated. Here we report docking simulations that identify a putative PL(−)-binding site, adjacent to the PIP(2)-binding site, generated by two lysine residues from neighbouring subunits. When either lysine is mutated to cysteine (K64C and K219C), channel activity is significantly decreased in cells and in reconstituted liposomes. Directly tethering K64C to the membrane by modification with decyl-MTS generates high PIP(2) sensitivity in liposomes, even in the complete absence of PL(−)s. The results provide a coherent molecular mechanism whereby PL(−) interaction with a discrete binding site results in a conformational change that stabilizes the high-affinity PIP(2) activatory site

KATP channels are necessary for glucose-dependent increases in amyloid-β and Alzheimer\u27s disease-related pathology

Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-β (Aβ) release, offering a mechanistic link between type 2 diabetes and Alzheimer\u27s disease (AD). Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with cellular excitability, play a role in AD pathogenesis. First, we demonstrate that KATP channel subunits Kir6.2/KCNJ11 and SUR1/ABCC8 were expressed on excitatory and inhibitory neurons in the human brain, and cortical expression of KCNJ11 and ABCC8 changed with AD pathology in humans and mice. Next, we explored whether eliminating neuronal KATP channel activity uncoupled the relationship between metabolism, excitability, and Aβ pathology in a potentially novel mouse model of cerebral amyloidosis and neuronal KATP channel ablation (i.e., amyloid precursor protein [APP]/PS1 Kir6.2-/- mouse). Using both acute and chronic paradigms, we demonstrate that Kir6.2-KATP channels are metabolic sensors that regulate hyperglycemia-dependent increases in interstitial fluid levels of Aβ, amyloidogenic processing of APP, and amyloid plaque formation, which may be dependent on lactate release. These studies identify a potentially new role for Kir6.2-KATP channels in AD and suggest that pharmacological manipulation of Kir6.2-KATP channels holds therapeutic promise in reducing Aβ pathology in patients with diabetes or prediabetes

MADNESS: A Multiresolution, Adaptive Numerical Environment for Scientific Simulation

MADNESS (multiresolution adaptive numerical environment for scientific simulation) is a high-level software environment for solving integral and differential equations in many dimensions that uses adaptive and fast harmonic analysis methods with guaranteed precision based on multiresolution analysis and separated representations. Underpinning the numerical capabilities is a powerful petascale parallel programming environment that aims to increase both programmer productivity and code scalability. This paper describes the features and capabilities of MADNESS and briefly discusses some current applications in chemistry and several areas of physics

Correlation of in Vitro Cytokine Responses with the Chemical Composition of Soil-Derived Particulate Matter

We treated human lung epithelial cells, type BEAS-2B, with 10–80 μg/cm(2) of dust from soils and road surfaces in the western United States that contained particulate matter (PM) < 2.5 μm aerodynamic diameter. Cell viability and cytokine secretion responses were measured at 24 hr. Each dust sample is a complex mixture containing particles from different minerals mixed with biogenic and anthropogenic materials. We determined the particle chemical composition using methods based on the U.S. Environmental Protection Agency Speciation Trends Network (STN) and the National Park Service Interagency Monitoring of Protected Visual Environments (IMPROVE) network. The functionally defined carbon fractions reported by the ambient monitoring networks have not been widely used for toxicology studies. The soil-derived PM(2.5) from different sites showed a wide range of potency for inducing the release of the proinflammatory cytokines interleukin-6 (IL-6) and IL-8 in vitro. Univariate regression and multivariate redundancy analysis were used to test for correlation of viability and cytokine release with the concentrations of 40 elements, 7 ions, and 8 carbon fractions. The particles showed positive correlation between IL-6 release and the elemental and pyrolyzable carbon fractions, and the strongest correlation involving crustal elements was between IL-6 release and the aluminum:silicon ratio. The observed correlations between low-volatility organic components of soil- and road-derived dusts and the cytokine release by BEAS-2B cells are relevant for investigation of mechanisms linking specific air pollution particle types with the initiating events leading to airway inflammation in sensitive populations

Looking for a needle in a haystack: inference about individual fitness components in a heterogeneous population

Studies of wild vertebrates have provided evidence of substantial differences in lifetime reproduction among individuals and the sequences of life history ‘states’ during life (breeding, nonbreeding, etc.). Such differences may reflect ‘fixed’ differences in fitness components among individuals determined before, or at the onset of reproductive life. Many retrospective life history studies have translated this idea by assuming a ‘latent’ unobserved heterogeneity resulting in a fixed hierarchy among individuals in fitness components. Alternatively, fixed differences among individuals are not necessarily needed to account for observed levels of individual heterogeneity in life histories. Individuals with identical fitness traits may stochastically experience different outcomes for breeding and survival through life that lead to a diversity of ‘state’ sequences with some individuals living longer and being more productive than others, by chance alone. The question is whether individuals differ in their underlying fitness components in ways that cannot be explained by observable ‘states’ such as age, previous breeding success, etc. Here, we compare statistical models that represent these opposing hypotheses, and mixtures of them, using data from kittiwakes. We constructed models that accounted for observed covariates, individual random effects (unobserved heterogeneity), first-order Markovian transitions between observed states, or combinations of these features. We show that individual sequences of states are better accounted for by models incorporating unobserved heterogeneity than by models including first-order Markov processes alone, or a combination of both. If we had not considered individual heterogeneity, models including Markovian transitions would have been the best performing ones. We also show that inference about age-related changes in fitness components is sensitive to incorporation of underlying individual heterogeneity in models. Our approach provides insight into the sources of individual heterogeneity in life histories, and can be applied to other data sets to examine the ubiquity of our results across the tree of life

Comparative effectiveness study of patient‐reported outcomes after proton therapy or intensity‐modulated radiotherapy for prostate cancer

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106701/1/cncr28536.pd

LUMINOS-102: Lerapolturev with and without α-PD- 1 in unresectable α-PD- 1 refractory melanoma

Lerapolturev (lera, formerly PVSRIPO) is a novel poliovirus based intratumoral immunotherapy that infects both cancer cells and antigen-presenting cells (APCs) via CD155, the poliovirus receptor. Lera has direct anticancer effects while also generating type I/III interferon-dominated inflammation and anti-tumor T-cell priming and activation via infection of local APCs. LUMINOS-102 (NCT04577807) is a multi-center, open-label, two-arm randomized Phase 2 study investigating the efficacy and safety of lera ± α-PD- 1 in patients with unresectable melanoma who failed prior α-PD- 1 therapy. Cross-over to the α-PD- 1 arm is permitted after progression, PR for ≥6 mo or 6 mo on treatment with SD. The maximum initial lera dose was 6x108 TCID50 /visit every 3 or 4 weeks (Q3/4 W). As of March 2022, the maximum lera dose was increased to 1.6 x 109 TCID50/visit, every week (QW) for 7 weeks (induction), followed by Q3/4 W dosing (maintenance). As of 20-Jun- 2022, 21 participants (10 male, 11 female, median 64 yrs) received lera (n = 14 at initial dose, Q3/4 W; n = 4 at increased dose, Q3/4 W; n = 3 at increased dose, QW) ± αPD-1. Five patients are currently on treatment. With the initial regimen, no objective responses and a CBR of 7% were observed. However, with the higher dose regimen, 1 complete response and a CBR of 71% (5/7) has been observed. Two of 4 participants with stable disease have evidence of response (1 with resolution of uninjected lung metastasis, 1 with decreased PET signal in injected and uninjected lesions receiving combination therapy). The only treatment related AE in \u3e1 pt was fatigue (19%, all grade 1 or 2). No dose-limiting toxicities or treatment-related SAEs were reported. Multiplex-IF analysis of on-treatment tumor biopsies will be presented. Lera ± αPD-1 is well tolerated, with early signs of efficacy at the higher dose level. Enrollment and randomization are ongoing