Metallic Pockets Research Articles

Discovery of Selective PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects by Targeting the Metal Pocket.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no ideal drugs. Our previous research demonstrated that phosphodiesterase 1 (PDE1) could be a promising target for the treatment of IPF. However, only a few selective PDE1 inhibitors are available, and the mechanism of recognition between inhibitors and the PDE1 protein is not fully understood. This study carried out a step-by-step optimization of a dihydropyrimidine hit Z94555858. By targeting the metal pocket of PDE1, a lead compound 3f was obtained, exhibiting an IC50 value of 11 nM against PDE1, moderate selectivity over other PDEs, and significant anti-fibrotic effects in bleomycin-induced pulmonary fibrosis rats. The structure-activity relationship study aided by molecular docking revealed that forming halogen bonds with water in the metal pocket greatly enhanced the PDE1 inhibition, providing a novel strategy for further rational design of PDE1 inhibitors.

The determination of CHARMM force field parameters for the Mg2+ containing HIV-1 integrase

The HIV integrase enzyme is a validated drug target. However, its potential has remained largely unexploited until recently due to lack of structural and mechanistic information. Its catalytic core domain (CCD) is crucial for the viral-human DNA integration making integrase an ideal target for inhibitor design. However, in order to do so, force field parameters for the integrase magnesium ion need to be established. Quantum mechanical calculations were used to derive force field parameters which were validated through molecular dynamics studies. Our results show that the parameters determined accurately maintain the integrity of the metal pocket of the integrase CCD.

Synthesis and molecular docking of new roflumilast analogues as preferential-selective potent PDE-4B inhibitors with improved pharmacokinetic profile

In the present work, we designed and synthesized new roflumilast analogues with preferential-selective PDE-4B inhibition activity and improved pharmacokinetic properties. The unsubstituted benzo[d]thiazol-2-yl and -6-yl benzamide derivatives (4a and 6a) showed both good potency and preferential selectivity for PDE-4B. More remarkably, 6c revealed 6 times preferential PDE-4B/4D selectivity with a significant increase of in vitro cAMP and good % inhibition of TNF-α concentration. In addition, the in vitro pharmacokinetics of 6c showed good metabolic stability with in vitro CLint (5.67 mL/min/kg) and moderate % plasma protein binding (53.71%). This was reflected onto increased in vivo exposure with a half-life greater than roflumilast by 3 folds (21 h) and a Cmax value of 113.958 ng/mL. Molecular docking attributed its good activity to its key binding interactions in PDE-4B active site with additional hydrogen bonding with amino acids lining the metal pocket. Summing up, 6c can be considered as suitable candidate for further investigation for the treatment of COPD.

Prediction of an arc-tunable Weyl Fermion metallic state in Mo(x)W(1-x)Te2.

A Weyl semimetal is a new state of matter that hosts Weyl fermions as emergent quasiparticles. The Weyl fermions correspond to isolated points of bulk band degeneracy, Weyl nodes, which are connected only through the crystal's boundary by exotic Fermi arcs. The length of the Fermi arc gives a measure of the topological strength, because the only way to destroy the Weyl nodes is to annihilate them in pairs in the reciprocal space. To date, Weyl semimetals are only realized in the TaAs class. Here, we propose a tunable Weyl state in MoxW1−xTe2 where Weyl nodes are formed by touching points between metallic pockets. We show that the Fermi arc length can be changed as a function of Mo concentration, thus tuning the topological strength. Our results provide an experimentally feasible route to realizing Weyl physics in the layered compound MoxW1−xTe2, where non-saturating magneto-resistance and pressure-driven superconductivity have been observed.

Failure of a Helicopter Main Rotor Blade

A military helicopter crash was investigated. The aircraft was flying at cruise speed in clear sky at 1000 feet over a flat area. The crew suddenly lost the control of the helicopter that crashed in the immediately causing fatal injuries to the whole crew. Four main rotor blades were found close to the impact point, while the fifth blade was found about 900 m before the wreck. Therefore efforts were directed to the failure of this blade that had apparently separated in the air. The rotor blade comprised a long hollow 6061-T6 aluminum alloy extrusion and 25 thin metallic pockets that provided the trailing edge airfoil shape. Visual examination of the fracture surface of the aluminum extrusion indicated fatigue crack growth followed by ductile overload separation. Examination by optical and electronic microscopy of the fatigue fracture revealed an abnormal incision that appeared to be the fracture origin site. The incision was about 2,3cm long and 190μm deep. Fatigue failure growth time was determined using fracture mechanics. Electronic microscopy equipped with X-EDS analyzer revealed the presence of iron in the incision. This evidence allowed to ascertain that the incision at the crack origin resulted from the use of an inappropriate tool used to remove pockets during maintenance activities. In addition to IBIS and in order to improve the safety of flights, NDTs were developed and then established every 200 flight hours.

Efficient solid rocket propulsion for access to space

Space launch activity is expected to grow in the next few years in order to follow the current trend of space exploitation for business purpose. Granting high specific thrust and volumetric specific impulse, and counting on decades of intense development, solid rocket propulsion is a good candidate for commercial access to space, even with common propellant formulations. Yet, some drawbacks such as low theoretical specific impulse, losses as well as safety issues, suggest more efficient propulsion systems, digging into the enhancement of consolidated techniques. Focusing the attention on delivered specific impulse, a consistent fraction of losses can be ascribed to the multiphase medium inside the nozzle which, in turn, is related to agglomeration; a reduction of agglomerate size is likely. The present paper proposes a model based on heterogeneity characterization capable of describing the agglomeration trend for a standard aluminized solid propellant formulation. Material microstructure is characterized through the use of two statistical descriptors (pair correlation function and near-contact particles) looking at the mean metal pocket size inside the bulk. Given the real formulation and density of a propellant, a packing code generates the material representative which is then statistically analyzed. Agglomerate predictions are successfully contrasted to experimental data at 5 bar for four different formulations.

Study of the glass transition on viscous-forming and powder materials using dynamic mechanical analysis

The investigation of the glass transition in materials that become too viscous or are difficult to prepare in a solid compact form, is not straightforward using dynamic mechanical analysis, DMA. In this work, metallic pockets are used to envelop samples in order to resolve the loss factor peak, tan δ, in the region of T g . Experiments with indium were carried out at different heating rates in order to correct the temperature in such isochronal measurements. The proof of concept of the utility of such methodology was done by investigating the glass transition dynamics of poly( d, l-lactic acid), PDLLA, a biodegradable amorphous polyester widely investigated for biomedical applications. The glass transition peaks obtained at scanning rates below 4 °C min −1 shifted to the same temperature region after correction. DMA tests on PDLLA at different frequencies allowed construction of a relaxation plot where the glass transition dynamics followed Vogel–Fulcher–Tamman–Hesse behaviour. Inclusion complexes, ICs, of PDLLA with α-cyclodextrin were obtained, exhibiting a very organized arrangement at the nano-scale level. DMA experiments on the ICs powder packed in the metallic pocket revealed a loss factor peak located at a higher temperature as compared with PDLLA, indicating that the segmental mobility of the polymer chains is highly restricted in this supra-molecular organization.

Angle-resolved photoemission study of the evolution of band structure and charge density wave properties inRTe3(R=Y, La, Ce, Sm, Gd, Tb, and Dy)

We present a detailed angle-resolved photoemission spectroscopy (ARPES) investigation of the $R{\text{Te}}_{3}$ family, which sets this system as an ideal ``textbook'' example for the formation of a nesting driven charge density wave (CDW). This family indeed exhibits the full range of phenomena that can be associated to CDW instabilities, from the opening of large gaps on the best nested parts of Fermi surface (up to 0.4 eV), to the existence of residual metallic pockets. ARPES is the best suited technique to characterize these features, thanks to its unique ability to resolve the electronic structure in $k$ space. An additional advantage of $R{\text{Te}}_{3}$ is that the band structure can be very accurately described by a simple two dimensional tight-binding (TB) model, which allows one to understand and easily reproduce many characteristics of the CDW. In this paper, we first establish the main features of the electronic structure by comparing our ARPES measurements with the linear muffin-tin orbital band calculations. We use this to define the validity and limits of the TB model. We then present a complete description of the CDW properties and of their strong evolution as a function of $R$. Using simple models, we are able to reproduce perfectly the evolution of gaps in $k$ space, the evolution of the CDW wave vector with $R$, and the shape of the residual metallic pockets. Finally, we give an estimation of the CDW interaction parameters and find that the change in the electronic density of states $n({E}_{F})$, due to lattice expansion when different $R$ ions are inserted, has the correct order of magnitude to explain the evolution of the CDW properties.

Origin of rapid oscillations in low-dimensional(TMTSF)2PF6

In order to clarify the origin of the "Rapid Oscillation" (RO) in (TMTSF)2PF6, we studied the magnetoresistance anisotropy in the Field Induced Spin Density Wave (FISDW) phase. We have found that in the FISDW insulating state, the Fermi surface is not totally gapped; the remaining 2D metallic pockets are quantized in magnetic field and give rise to the RO. Decreasing temperature does not change the size and orientation of the closed pockets, rather, it causes depopulation of the delocalized states in favor of the localized ones, resulting in the disappearance of the RO.

Rapid Oscillations in (TMTSF)2PF6

In order to clarify the origin of the “Rapid Oscillation” (RO) in (TMTSF)2PF6, we studied the magnetoresistance anisotropy in the Field-Induced Spin Density Wave (FISDW) phase. We have found that in the FISDW insulating state, the Fermi surface is not totally gapped; the remaining 2D metallic pockets are quantized in magnetic field and give rise to the RO. Decreasing temperature does not change the size and orientation of the closed pockets, rather, it causes depopulation of the delocalized states in favor of the localized ones, resulting in the disappearance of the RO.

Modeling the charge distribution at metal sites in proteins for molecular dynamics simulations

Almost half of the proteome of living organisms is constituted of metalloproteins. Unfortunately, the ability of the current generation of molecular dynamics pairwise-additive forcefields to properly describe metal pockets is severely lacking due to the intrinsic difficulty of handling polarization and charge transfer contributions. In order to improve the description of metalloproteins, a simple reparameterization strategy is proposed herein that does not involve artificial constraints. Specifically, a non-bonded quantum mechanical-based model is used to capture the mean polarization and charge transfer contributions to the interatomic forces within the metal site. The present approach is demonstrated to provide enough accuracy to maintain the integrity of the metal pocket for a variety of metalloproteins during extended (multi-nanosecond) molecular dynamics simulations. The method enables the sampling of small conformational changes and the relaxation of local frustrations in NMR structures.

Nested Fermi Surface and Electronic Instability inCa3Ru2O7

High-resolution angular resolved photoemission data reveal well-defined quasiparticle bands of unusually low weight, emerging in line with the metallic phase of Ca(3)Ru(2)O(7) below approximately 30 K . At the bulk structural phase transition temperature of 48 K, we find clear evidence for an electronic instability, gapping large parts of the underlying Fermi surface that appears to be nested. Metallic pockets are found to survive in the small, non-nested sections, constituting a low-temperature Fermi surface with 2 orders of magnitude smaller volume than in all other metallic ruthenates. The Fermi velocities and volumes of these pockets are in agreement with the results of complementary quantum oscillation measurements on the same crystal batches.

Ellenore Flood Responds: An Informal Letter of Thanks From the Client

Dear Article Authors: I want to thank you all for the time and energy you spent reading and interpreting my interest inventories. Few people have the opportunity to be the subject of such thought-provoking analyses as these, especially from counselors of your caliber. As I'm sure you've guessed, I'm rarely at a loss for words, but words wouldn't do justice to the gratitude I feel toward Dr. Savickas for this opportunity. I want you all to know that I truly appreciate your comments, and thought you might like to know the direction I have chosen. Before I tell you, I will have to admit that I felt a bit like a live animal in a science experiment laid open to be probed when I sat down to read all of these. Each one of you hit something so perfectly that I was astounded. These articles (and the career counseling process) remind me of the board game called Operation. The red buzzer nose of the game board patient would sound in alarm when my shaky tweezers hit the metal pocket holding the funny bone. Similarly, the buzzer in my brain went off each time I read something in these articles that not only applied to me, but enlightened me. Some were painful, but always helpful. Following is my response to each article. In the Hartung article assessing the C-DAC approach, I was struck by the difference in make versus making decisions. I am a bad decision maker, and this is something I need to work on. But I especially liked the shopping metaphor, because it spoke directly to me as an English teacher and a shopper. It was a perfect summary of what I have been doing for the last 10 years. Recently, I have started buying. I am learning to meet people in my field, which has made me much more interested in the direction I am going. To continue the metaphor, I am considering throwing away the sales slip that will allow me to exchange my current career path for the old one of high school teaching. Not only am I starting to realize that I can't go back (as a PhD, I will price myself out of the market), but that I really don't want to. As you say, I am beginning to consider how to refocus so that if I want, secondary school students can in some way also be a part of my future. The Prediger and Schmertz article assessed the UNIACT. Although I have little doubt this was a very useful discussion of the UNIACT from a counselor's point of view, it did not offer much that I could use. I did like the World-of-Work Map, and I think it could be useful for someone at the beginning stages of the career decision-making process. The Campbell Interest and Skill Survey was discussed by Dr. Boggs. In interpreting the CISS, she hit the nail on the head when she assessed the Interpreting and Creating scores, because corporate trainer is high on the option list. In the Animal Care Bs, Dr. Boggs wondered if I had a pet. I don't, but I would love one! I found the style of the discussion portion that followed extremely helpful (probably due to my verbal nature). Most notable was that Dr. Boggs was the only counselor who brought up the issue of motherhood and how that might intermingle with my career choices. Other notable comments included her confirmation that a firm sense of direction is vitally important during counseling. I get extremely frustrated when that does not happen. Also, I thought it was interesting that she asked questions of herself in terms of the counselor-counselee relationship and the importance of my expectations of her as a counselor. Finally, Dr. Boggs unknowingly picked up on the shopping metaphor when she concluded with her emphasis that career development is a series of choices, not one choice. But her final sentence recalled the most salient point mentioned, which is the balance between career and personal life that I am constantly trying to maintain. In interpreting the Strong Interest Inventory, Dr. Prince hit on a number of issues that came up in my actual counseling sessions, such as the importance of learning in my life and how I would maintain that if I didn't pursue the PhD. …