Development of selective inhibitors of phosphatidylinositol 3-kinase C2α

Phosphatidylinositol 3-kinase type 2α (PI3KC2α) and related class II PI3K isoforms are of increasing biomedical interest because of their crucial roles in endocytic membrane dynamics, cell division and signaling, angiogenesis, and platelet morphology and function. Herein we report the development and characterization of PhosphatidylInositol Three-kinase Class twO INhibitors (PITCOINs), potent and highly selective small-molecule inhibitors of PI3KC2α catalytic activity. PITCOIN compounds exhibit strong selectivity toward PI3KC2α due to their unique mode of interaction with the ATP-binding site of the enzyme. We demonstrate that acute inhibition of PI3KC2α-mediated synthesis of phosphatidylinositol 3-phosphates by PITCOINs impairs endocytic membrane dynamics and membrane remodeling during platelet-dependent thrombus formation. PITCOINs are potent and selective cell-permeable inhibitors of PI3KC2α function with potential biomedical applications ranging from thrombosis to diabetes and cancer

Heat Exchange Modeling of a Grate Clinker Cooler and Entropy Production Analysis

The concept of the exergy analysis is applied to a grate cooler of a cement production facility. The cooling of the clinker is modelled by a gas-solid series of cross-current contacting stages fully mixed for the calculation of the temperatures of the clinker and the air with their thermodynamic properties along the cooler. The equation of the production of entropy developed in the case of this representation reveals various adimensional parameters. The study of the sensitivity of the entropy generation number by tests of simulation in real operating conditions of the cooler shows the importance of the inlet temperature ratio and the number of stages cross-current contacting

To Flee or Not to Flee: How Age, Reproductive Phase, and Mate Presence Affect White Stork Flight Decisions

Recognizing, assessing, and responding to threats is critical for survival in the wild. Birds, especially in their role as parents, must decide whether to flee or delay flight when threatened. This study examines how age, reproductive stage, and the presence of a mate influence flight initiation distance (FID) and nest recess duration in white storks. Analyzing the data with a generalized additive mixed model (GAMM), we found significant correlations between FID and age, reproductive stage, and presence of a mate. These results suggest that the trade-off between current and future reproduction shifts during critical breeding periods, such as incubation and nestling care. To increase breeding success, White Storks appear willing to take risks and extend their stay in the nest when offspring are most valuable and vulnerable. In the presence of a mate, individuals leave the nest earlier, suggesting possible sexual conflict over parental care. The duration of nest abandonment is consistent with FID, except for age. These results illustrate how parental age, brood value, vulnerability, and sexual dynamics influence white stork flight decisions in complex ways. Understanding these dynamics enriches our knowledge of bird behavior and adaptations to environmental challenges and highlights the complexity of parental decision making

A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels

Potassium (K+) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K+ channels gated at their selectivity filter (SF), including many two-pore domain K+ (K2P) channels, voltage-gated hERG (human ether-à-go-go–related gene) channels and calcium (Ca2+)–activated big-conductance potassium (BK)–type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K+ occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K+ channel activators and highlight a filter gating machinery that is conserved across different families of K+ channels with implications for rational drug design.</jats:p

A pharmacological master key mechanism that unlocks the selectivity filter gate in K⁺ channels.

Potassium (K+) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K+ channels gated at their selectivity filter (SF), including many two-pore domain K+ (K2P) channels, voltage-gated hERG (human ether-à-go-go-related gene) channels and calcium (Ca2+)-activated big-conductance potassium (BK)-type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K+ occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K+ channel activators and highlight a filter gating machinery that is conserved across different families of K+ channels with implications for rational drug design