Genetic regulation of pituitary gland development in human and mouse

Normal hypothalamopituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke’s pouch. These factors dictate organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Abnormalities in these processes are associated with congenital hypopituitarism, a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia, combined pituitary hormone deficiencies, and isolated hormone deficiencies, of which the commonest is GH deficiency. The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 yr, based mainly on naturally occurring and transgenic animal models. Mutations in genes encoding both signaling molecules and transcription factors have been implicated in the etiology of hypopituitarism, with or without other syndromic features, in mice and humans. To date, mutations in known genes account for a small proportion of cases of hypopituitarism in humans. However, these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. This review attempts to describe the complexity of pituitary development in the rodent, with particular emphasis on those factors that, when mutated, are associated with hypopituitarism in humans

Search for pair-produced resonances decaying to quark pairs in proton-proton collisions at root s=13 TeV

A general search for the pair production of resonances, each decaying to two quarks, is reported. The search is conducted separately for heavier resonances (masses above 400 GeV), where each of the four final-state quarks generates a hadronic jet resulting in a four-jet signature, and for lighter resonances (masses between 80 and 400 GeV), where the pair of quarks from each resonance is collimated and reconstructed as a single jet resulting in a two-jet signature. In addition, a b-tagged selection is applied to target resonances with a bottom quark in the final state. The analysis uses data collected with the CMS detector at the CERN LHC, corresponding to an integrated luminosity of 35.9 fb(-1), from proton-proton collisions at a center-of-mass energy of 13 TeV. The mass spectra are analyzed for the presence of new resonances, and are found to be consistent with standard model expectations. The results are interpreted in the framework of R-parity-violating supersymmetry assuming the pair production of scalar top quarks decaying via the hadronic coupling lambda ''(312) or lambda ''(323) and upper limits on the cross section as a function of the top squark mass are set. These results probe a wider range of masses than previously explored at the LHC, and extend the top squark mass limits in the (t) over tilde -> qq' scenario.Peer reviewe

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Understanding the Solubility of Acetaminophen in 1‑<i>n</i>‑Alkyl-3-methylimidazolium-Based Ionic Liquids Using Molecular Simulation

During the manufacturing of pharmaceutical compounds, solvent mixtures are commonly used, where the addition of a cosolvent allows for the tuning of the intermolecular interactions present in the system. Here we demonstrate how a similar effect can be accomplished using a room temperature ionic liquid. The pharmaceutical compound acetaminophen is studied in 21 common ionic liquids composed of a 1-<i>n</i>-alkyl-3-methylimidazolium cation with 1 of 7 anions. Using the acetate anion, we predict a large enhancement in solubility of acetaminophen relative to water. We show how this is caused by a synergistic effect of favorable interactions between the ionic liquid and the phenyl, hydroxyl and amide groups of acetaminophen, demonstrating how the ionic liquid cation and anion may be chosen to preferentially solvate different functional groups of complex pharmaceutical compounds. Additionally, while the use of charge scaling in ionic liquid force fields has previously been found to have a minute effect on ionic liquid structural properties, we find it appreciably affects the computed solvation free energy of acetaminophen, which in turn affects the predicted solubility

Plexciton Quenching by Resonant Electron Transfer from Quantum Emitter to Metallic Nanoantenna

Coupling molecular excitons and localized surface plasmons in hybrid nanostructures leads to appealing, tunable optical properties. In this respect, the knowledge about the excitation dynamics of a quantum emitter close to a plasmonic nanoantenna is of importance from fundamental and practical points of view. We address here the effect of the excited electron tunneling from the emitter into a metallic nanoparticle(s) in the optical response. When close to a plasmonic nanoparticle, the excited state localized on a quantum emitter becomes short-lived because of the electronic coupling with metal conduction band states. We show that as a consequence, the characteristic features associated with the quantum emitter disappear from the optical absorption spectrum. Thus, for the hybrid nanostructure studied here and comprising quantum emitter in the narrow gap of a plasmonic dimer nanoantenna, the quantum tunneling might quench the plexcitonic states. Under certain conditions the optical response of the system approaches that of the individual plasmonic dimer. Excitation decay via resonant electron transfer can play an important role in many situations of interest such as in surface-enhanced spectroscopies, photovoltaics, catalysis, or quantum information, among others

Understanding the Solubility of Acetaminophen in 1‑<i>n</i>‑Alkyl-3-methylimidazolium-Based Ionic Liquids Using Molecular Simulation

During the manufacturing of pharmaceutical compounds, solvent mixtures are commonly used, where the addition of a cosolvent allows for the tuning of the intermolecular interactions present in the system. Here we demonstrate how a similar effect can be accomplished using a room temperature ionic liquid. The pharmaceutical compound acetaminophen is studied in 21 common ionic liquids composed of a 1-<i>n</i>-alkyl-3-methylimidazolium cation with 1 of 7 anions. Using the acetate anion, we predict a large enhancement in solubility of acetaminophen relative to water. We show how this is caused by a synergistic effect of favorable interactions between the ionic liquid and the phenyl, hydroxyl and amide groups of acetaminophen, demonstrating how the ionic liquid cation and anion may be chosen to preferentially solvate different functional groups of complex pharmaceutical compounds. Additionally, while the use of charge scaling in ionic liquid force fields has previously been found to have a minute effect on ionic liquid structural properties, we find it appreciably affects the computed solvation free energy of acetaminophen, which in turn affects the predicted solubility

Insights on the Solubility of CO₂ in 1‑Ethyl-3-methylimidazolium Bis(trifluoromethylsulfonyl)imide from the Microscopic Point of View

Emissions of greenhouse gases due to human activities have been well documented as well as the effects on global warming resulting from it. Efforts to reduce greenhouse gases at the source are crucial to curb climate change, but due to insignificant economic incentives to reduce usage of fossil fuels, not a lot of progress has been made by this route. This necessitates additional measures to reduce the occurrence of greenhouse gases in the atmosphere. Here we used theoretical methods to study the solubility of carbon dioxide in ionic liquids (ILs) since sequestration of CO₂ in ILs has been proposed as a possible technology for reducing the emissions of CO₂ to the atmosphere. Ionic liquids form a class of solvents with melting temperatures below 100 °C and, due to very low vapor pressures, which are not volatile. We have performed molecular dynamics (MD) simulations of 1-ethyl-3-methylimidazolium (C₂mim) bis­(trifluoromethylsulfonyl)­imide (Tf₂N) and its mixtures with carbon dioxide in order to investigate the CO₂ concentration effect on the CO₂–cation and CO₂–anion interactions. A systematic investigation of CO₂ concentration effects on resulting equilibrium liquid structure, and the local environment of the ions is provided. The Quantum Theory of Atoms in Molecules (QTAIM) was used to determine the interaction energy for CO₂–cation and CO₂–anion complexes from uncorrelated structures derived from MD simulations. A spatial distribution function analysis demonstrates the specific interactions between CO₂ and the ionic liquid. Our findings indicate that the total volume of the system increases with the CO₂ concentration, with a molar volume of CO₂ of about 0.038 L/mol, corresponding to liquid CO₂ under a pressure of 100 bar. In other words, the IL effectively pressurizes the CO₂ inside its matrix. The thermodynamics of CO₂ solvation in C2 min-Tf₂N were computed using free energy techniques, and the solubility of CO₂ is found to be higher in this IL (−3.7 ± 1 kcal/mol) than in water (+0.2 kJ/mol), predominantly due to anion–CO₂ interactions

Stability, Structure, and Electronic Properties of the Pyrite/Arsenopyrite Solid–Solid Interface–A DFT Study

Pyrite is the most common sulfide in the Earth. In the presence of arsenopyrite its oxidation is delayed, and instead, the arsenopyrite increases its oxidation rate, releasing As­(III) and As­(V) species in the medium. DFT/plane waves calculations were performed on pyrite/arsenopyrite interface models to understand the stability, structure, and electronic properties of the interface. This is the first step to understand the influence of the inlaid arsenopyrite in the pyrite oxidation mechanism. The interface is slightly stressed with minor changes in the bond lengths and lattice parameters with respect to the pure phases. The work of adhesion and the formation energy indicate that the miscibility of the two phases is not favorable, explaining the presence of large domains of either pyrite or arsenopyrite forming bulk granular regions. The valence band of the pyrite/arsenopyrite interface has large contributions from the pyrite phase, while the conduction band has large contributions from the arsenopyrite. This is consistent with the pyrite as cathode and arsenopyrite as anode in a galvanic contact. Furthermore, the interface formation shifts the valence states upward and decreases the band gap, facilitating interfacial electron transfer