Analysis of Dynamic Magnetoelastic Coupling in Mechanically Driven Magnetoelectric Antennas.

Mechanically driven magnetoelectric antennas are a promising new technology that enable a reduction in antenna size by many orders of magnitude, as compared to conventional antennas. The magnetoelastic coupling in these antennas, a phenomenon playing a direct role in determining performance, has been modeled using approaches that are severely lacking in both accuracy and tractability. In response to this problem, we take a physics-based approach to the analysis of magnetoelastic coupling. We find that certain directions of applied stress will maximize the coupling and we derive general expressions to quantify it. Our results are applied in comprehensive simulations that demonstrate the dynamic nature of the coupling as well as the impact of various operating conditions and material properties. Our work contributes analytical expressions and associated insight that can serve not only as guidelines for the design of mechanically driven magnetoelectric antennas, but also as stepping stones towards the development of more accurate models.

Nitrile-containing pharmaceuticals: target, mechanism of action, and their SAR studies.

The nitrile group is an important functional group widely found in both pharmaceutical agents and natural products. More than 30 nitrile-containing pharmaceuticals have been approved by the FDA for the management of a broad range of clinical conditions in the last few decades. Incorporation of a nitrile group into lead compounds has gradually become a promising strategy in rational drug design as it can bring additional benefits including enhanced binding affinity to the target, improved pharmacokinetic profile of parent drugs, and reduced drug resistance. This paper reviews the existing drugs with a nitrile moiety that have been approved or in clinical trials, involving their targets, molecular mechanism of pharmacology and SAR studies, and classifies them into different categories based on their clinical usages.

Structure of PDE3A-SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells.

Molecular glues are a class of small molecular drugs that mediate protein-protein interactions, that induce either the degradation or stabilization of target protein. A structurally diverse group of chemicals, including 17-ß-estradiol (E2), anagrelide, nauclefine, and DNMDP, induces apoptosis by forming complexes with phosphodiesterase 3A (PDE3A) and Schlafen 12 protein (SLFN12). They do so by binding to the PDE3A enzymatic pocket that allows the compound-bound PDE3A to recruit and stabilize SLFN12, which in turn blocks protein translation, leading to apoptosis. In this work, we report the high-resolution cryo-electron microscopy structure of PDE3A-SLFN12 complexes isolated from cultured HeLa cells pre-treated with either anagrelide, or nauclefine, or DNMDP. The PDE3A-SLFN12 complexes exhibit a butterfly-like shape, forming a heterotetramer with these small molecules, which are packed in a shallow pocket in the catalytic domain of PDE3A. The resulting small molecule-modified interface binds to the short helix (E552-I558) of SLFN12 through hydrophobic interactions, thus "gluing" the two proteins together. Based on the complex structure, we designed and synthesized analogs of anagrelide, a known drug used for the treatment of thrombocytosis, to enhance their interactions with SLFN12, and achieved superior efficacy in inducing apoptosis in cultured cells as well as in tumor xenografts.

Unexpected Substituent Effects in Spiro-Compound Formation: Steering N-Aryl Propynamides and DMSO toward Site-Specific Sulfination in Quinolin-2-ones or Spiro[4,5]trienones.

A highly substituent-dependent rearrangement allows for the novel and SOCl2-induced divergent synthesis of 3-methylthioquinolin-2-ones and 3-methylthiospiro[4.5]trienones through intramolecular electrophilic cyclization of N-aryl propyamides. DMSO acts as both solvent and sulfur source, and use of DMSO-h6/d6 enables the incorporation of SCH3 or SCD3 moieties to the 3-position of the heterocyclic framework. Different para-substituents trigger divergent reaction pathways leading to the formation of quinolin-2-ones for mild substituents and spiro[4,5]trienones for both electron-withdrawing and -donating substituents, respectively. On the basis of both computational and experimental results, a new mechanism has been put forward that accounts for the exclusive spirolization/defluorination process and the surprising substituent effects.

Magnetic Pendulum Arrays for Efficient ULF Transmission.

The frequencies lying between 300 Hz to 3 kHz have been designated as Ultra Low Frequency (ULF) with corresponding wavelengths from 1000 Km to 100 Km. Although ULF has very low bandwidth it is very reliable, penetrating and difficult to jam which makes it a great choice for communication in underwater and underground environments. Small and portable ULF antennas within a diameter of 1 meter would operate under an electrical length on the order of 10-4 to 10-6 wavelengths in free space, making them very inefficient because of fundamental limits on radiation from electrically small antennas. To overcome this problem, Mechanical Antennas or 'Mechtennas' for Ultra Low Frequency Communications have been proposed recently. For efficient generation of ULF radiation, we propose a portable electromechanical system called a Magnetic Pendulum Array (MPA). A proof of concept demonstration of the system at 1.03 kHz is presented. The theory and experimental results demonstrate that such a system can achieve a significantly higher quality factor than conventional coils and thus order of magnitude higher transmission efficiency. The concept can be easily scaled to the ULF range of frequencies.

Replacement of Protein Binding-Site Waters Contributes to Favorable Halogen Bond Interactions.

Halogen bond interaction between a protein electronegative atom and a ligand halogen atom is increasingly attracting attention in the field of structure-based drug design. Nevertheless, gaps in understanding make it desirable to better examine the role of forces governing the formation of favorable halogen bond interactions, and the development of effective and efficient computational approaches to "design in" favorable halogen bond interactions in lead optimization process are warranted. Here, we analyzed the binding-site water properties of crystal structures with characterized halogen bond interactions between ligand halogen atoms and protein backbone carbonyl groups and, thus, found that halogen atoms involved in halogen bond interactions frequently replace calculated binding-site waters upon ligand binding. Moreover, we observed that the preferential directionality of halogen bond interactions aligns well with the orientations of these replaced waters, and these replaced waters exhibited differential energetic characteristics as compared to waters that are displaced by halogen atoms that do not form halogen bond interactions. Our discovery that replacement of calculated binding-site waters contributes to the formation of favorable halogen bond interactions suggests a practical approach for rational drug design utilizing halogen bond interactions with protein backbone carbonyl groups.

Modeling and Experimental Research on Resistance Spot Welded Joints for Dual-Phase Steel.

Dual-phase steel has been employed in the automotive industry as it has the advantages of high strength, satisfying ductility, low yield ratio, and so on. A novel framework for the weld nugget size prediction and control using finite element modeling and experimental research was proposed in this paper. The two-dimensional axisymmetric numerical analysis model was established and the phase transition on thermal expansion coefficient was taken into account. The whole welding process was simulated and discussed using thermal elastic-plastic theory. To validate the predictive methods of developed weld nugget size and confirmation experiments were implemented with the same input parameters in the ranges of process parameters. The simulated weld nugget sizes were in good agreement with the experimental results except for extreme welding conditions. The microstructure of the welding zone was also investigated based on metallographic experiments and temperature field analysis. The welding parameters were adjusted using the model proposed in this paper so as to obtain the nugget size with pull out failure mode.

A new hypervalent iodine(iii/v) oxidant and its application to the synthesis of 2H-azirines.

The reaction of o-nitroiodobenzene and mCPBA in acetic acid was found to afford a novel hypervalent iodine compound, in the structure of which both iodine(iii) and iodine(v) moieties coexist. The nitro groups at the ortho phenyl positions were found to be crucial in stabilizing this uncommon structure. This novel hypervalent iodine(iii/v) oxidant is proved to be effective in realizing the synthesis of 2-unsubstitued 2H-azirines via intramolecular oxidative azirination, which could not be efficiently achieved by the existing known hypervalent iodine reagents.

A survey of the role of nitrile groups in protein-ligand interactions.

In classical medicinal chemistry, nitrile groups were commonly considered as bioisosteres of carbonyl, hydroxyl and carboxyl groups, as well as halogen atoms. However, there is a lack of in-depth understanding about the structural and energetic characteristics of nitrile groups in protein-ligand interactions. Here, we have surveyed the Protein Data Bank and ChEMBL databases with the goal of characterizing such protein-ligand interactions for nitrile-containing compounds. We discuss the versatile roles of nitrile groups in improving binding affinities, and give special attention to examples of displacing and mimicking binding-site waters by nitrile groups. We expect that this review article will further inspire medicinal chemists to exploit nitrile groups rationally in structure-based drug design.

Exploring Halogen Bonds in 5-Hydroxytryptamine 2B Receptor-Ligand Interactions.

Here, we predicted the potential halogen bonding interaction between compound 2 and the 5-hydroxytryptamine 2B (5-HT2B) receptor and systematically assessed this interaction via structure-activity relationship analysis and molecular dynamics simulations. A physics-based computational protocol was then developed to further explore the opportunity of "designing in" halogen bonding interactions in structure-based ligand design for the 5-HT2B receptor, which not only facilitated the identification of previously uncharacterized halogen bonds in known 5-HT2B ligands but also enabled the rational design of halogen bonding interactions for the optimization of 5-HT2B ligands. As a proof-of-concept, a series of halogen-substituted analogues of doxepin was synthesized and evaluated, which showed improved in vitro and in vivo potency.

Ultra-Wide Band Non-reciprocity through Sequentially-Switched Delay Lines.

Achieving non-reciprocity through unconventional methods without the use of magnetic material has recently become a subject of great interest. Towards this goal a time switching strategy known as the Sequentially-Switched Delay Line (SSDL) is proposed. The essential SSDL configuration consists of six transmission lines of equal length, along with five switches. Each switch is turned on and off sequentially to distribute and route the propagating electromagnetic wave, allowing for simultaneous transmission and receiving of signals through the device. Preliminary experimental results with commercial off the shelf parts are presented which demonstrated non-reciprocal behavior with greater than 40 dB isolation from 200 KHz to 200 MHz. The theory and experimental results demonstrated that the SSDL concept may lead to future on-chip circulators over multi-octaves of frequency.