We previously showed that the anticancer drug imatinib mesylate (IMT, trade name: Gleevec) and a chemically distinct compound, DV2-103 (a kinase-inactive derivative of the potent Abl and Src kinase inhibitor, PD173955) lower Aβ levels at low micromolar concentrations primarily through a lysosome-dependent mechanism that renders APP less susceptible to proteolysis by BACE1 without directly inhibiting BACE1 enzymatic activity, or broadly inhibiting the processing of other BACE1 substrates. Additionally, IMT indirectly inhibits γ-secretase and stimulates autophagy, and thus may decrease Aβ levels through multiple pathways. In two recent studies we demonstrated similar effects on APP metabolism caused by derivatives of IMT and DV2-103. In the present study, we synthesized and tested radically altered IMT isomers (IMTi’s) that possess medium structural similarity to IMT. Independent of structural similarity, these isomers manifest widely differing potencies in altering APP metabolism. These will enable us to choose the most potent isomers for further derivatization.

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder characterized by the accumulation of β-amyloid (Aβ), C99, and Tau in vulnerable areas of the brain. Despite extensive research, current strategies to lower Aβ levels have shown limited efficacy in slowing the cognitive decline associated with AD. Recent findings suggest that C99 may also play a crucial role in the pathogenesis of AD. Our laboratory has discovered that CK1γ2 phosphorylates Presenilin 1 at the γ-secretase complex, leading to decreased C99 and Aβ levels. Thus, CK1γ2 activation appears as a promising therapeutic target to lower both C99 and Aβ levels. In this study, we demonstrate that CK1γ2 is inhibited by intramolecular autophosphorylation and describe a high-throughput screen designed to identify inhibitors of CK1γ2 autophosphorylation. We hypothesize that these inhibitors could lead to CK1γ2 activation and increased PS1-Ser367 phosphorylation, ultimately reducing C99 and Aβ levels. Using cultured cells, we investigated the impact of these compounds on C99 and Aβ concentrations and confirmed that CK1γ2 activation effectively reduced their levels. Our results provide proof of concept that CK1γ2 is an attractive therapeutic target for AD. Future studies should focus on the identification of specific compounds that can inhibit CK1γ2 autophosphorylation and evaluate their efficacy in preclinical models of AD. These studies will pave the way for the development of novel therapeutics for the treatment of AD.

Non-Hermitian Hamiltonians respecting parity–time symmetry are well known to be associated with real spectrum, so long as 𝒫𝒯 symmetry is exact or unbroken, with energies turning to complex conjugate pairs as this symmetry breaks down spontaneously. Such potentials are characterised by an even real part and an odd imaginary part. However, exactly solvable quantum mechanical models are very few. In this work, we conduct an exact analytical study of a new, periodic, 𝒫𝒯 -symmetric potential. The energies are observed to be real always, as there is no scope for spontaneous breakdown of 𝒫𝒯 symmetry. Using the principles of supersymmetric quantum mechanics, we find its partner Hamiltonian, sharing the same energy spectrum, with the possible exception of the ground state. Incidentally, the partner is also 𝒫𝒯 symmetric. Using Mathematica, we plot the exact eigenfunctions of both the partner Hamiltonians. Additionally, supersymmetric quantum mechanics (SUSY QM) helps us to find a totally new exactly solvable, non-trivial Hamiltonian, with the same energy spectrum.

Inhibitors of integrin αVβ3 have therapeutic promise for a variety of diseases. Most αVβ3-targeting small molecules patterned after the RGD motif are partial agonists because they induce a high-affinity, ligand-binding conformation and prime the receptor to bind the ligand without an activating stimulus, in part via a charge-charge interaction between their aspartic acid carboxyl group and the metal ion in the metal-ion-dependent adhesion site (MIDAS). Building upon our previous studies on the related integrin αIIbβ3, we searched for pure αVβ3 antagonists that lack this typical aspartic acid carboxyl group and instead engage through direct binding to one of the coordinating residues of the MIDAS metal ion, specifically β3 E220. By in silico screening of two large chemical libraries for compounds interacting with β3 E220, we indeed discovered a novel molecule that does not contain an acidic carboxyl group and does not induce the high-affinity, ligand-binding state of the receptor. Functional and structural characterization of a chemically optimized version of this compound led to the discovery of a novel small-molecule pure αVβ3 antagonist that (i) does not prime the receptor to bind the ligand and does not induce hybrid domain swing-out or receptor extension as judged by antibody binding and negative-stain electron microscopy, (ii) binds at the RGD-binding site as predicted by metadynamics rescoring of induced-fit docking poses and confirmed by a cryo-electron microscopy structure of the compound-bound integrin, and (iii) coordinates the MIDAS metal ion via a quinoline moiety instead of an acidic carboxyl group.

A theoretical study is presented for the propagation of Dust Ion Acoustic Waves in an unmagnetized four-component plasma, consisting of Maxwellian negative ions, cold mobile positive ions, $\kappa$-distributed electrons and positively charged dust grains. Based on the characteristics of Sagdeev pseudopotential and phase portraits, three types of nonlinear waves are observed --- solitons, double layers and supersolitons. The conditions for the existence of such nonlinear waves are highly sensitive to the plasma parameters. The results obtained in this study may be of wide relevance in the field of space plasma as well as ultrasmall semiconductor devices in the laboratory.

Amyloid-beta peptides generated by β-secretase- and γ-secretase-mediated successive cleavage of amyloid precursor protein are believed to play a causative role in Alzheimer's disease. Thus, reducing amyloid-beta generation by modulating γ-secretase remains a promising approach for Alzheimer's disease therapeutic development. Here, we screened fruit extracts of Ligustrum lucidum Ait. (Oleaceae) and identified active fractions that increase the C-terminal fragment of amyloid precursor protein and reduce amyloid-beta production in a neuronal cell line. These fractions contain a mixture of two isomeric pentacyclic triterpene natural products, 3-O-cis- or 3-O-trans-p-coumaroyl maslinic acid (OCMA), in different ratios. We further demonstrated that trans-OCMA specifically inhibits γ-secretase and decreases amyloid-beta levels without influencing cleavage of Notch. By using photoactivatable probes targeting the subsites residing in the γ-secretase active site, we demonstrated that trans-OCMA selectively affects the S1 subsite of the active site in this protease. Treatment of Alzheimer's disease transgenic model mice with trans-OCMA or an analogous carbamate derivative of a related pentacyclic triterpene natural product, oleanolic acid, rescued the impairment of synaptic plasticity. This work indicates that the naturally occurring compound trans-OCMA and its analogues could become a promising class of small molecules for Alzheimer's disease treatment.

Tafamidis, 1, a potent transthyretin kinetic stabilizer, weakly inhibits the γ-secretase enzyme in vitro. We have synthesized four amide derivatives of 1. These compounds reduce production of the Aβ peptide in N2a695 cells but do not inhibit the γ-secretase enzyme in cell-free assays. By performing fluorescence correlation spectroscopy, we have shown that TTR inhibits Aβ oligomerization and that addition of tafamidis or its amide derivative does not affect TTR's ability to inhibit Aβ oligomerization. The piperazine amide derivative of tafamidis (1a) efficiently penetrates and accumulates in mouse brain and undergoes proteolysis under physiological conditions in mice to produce tafamidis.

BACKGROUND:Parvalbumin (PV)-expressing interneurons are important for cognitive and emotional behaviors. These neurons express high levels of p11, a protein associated with depression and action of antidepressants.METHODS:We characterized the behavioral response to subthreshold stress in mice with conditional deletion of p11 in PV cells. Using chemogenetics, viral-mediated gene delivery, and a specific ion channel agonist, we studied the role of dentate gyrus PV cells in regulating anxiety-like behavior and resilience to stress. We used electrophysiology, imaging, and biochemical studies in mice and cells to elucidate the function and mechanism of p11 in dentate gyrus PV cells.RESULTS:p11 regulates the subcellular localization and cellular level of the potassium channel Kv3.1 in cells. Deletion of p11 from PV cells resulted in reduced hippocampal level of Kv3.1, attenuated capacity of high-frequency firing in dentate gyrus PV cells, and altered short-term plasticity at synapses on granule cells, as well as anxiety-like behavior and a pattern separation deficit. Chemogenetic inhibition or deletion of p11 in these cells induced vulnerability to depressive behavior, whereas upregulation of Kv3.1 in dentate gyrus PV cells or acute activation of Kv3.1 using a specific agonist induced resilience to depression.CONCLUSIONS:The activity of dentate gyrus PV cells plays a major role in the behavioral response to novelty and stress. Activation of the Kv3.1 channel in dentate gyrus PV cells may represent a target for the development of cell-type specific, fast-acting antidepressants.

A theoretical study is presented for the oblique propagation of linear and nonlinear ion acoustic waves in a dense electron-ion quantum plasma, as that found in dense astrophysical objects like white dwarfs, rotating around an axis at an angle θ with the direction of the constant magnetic field B→=B0ẑ. In the absence of exact analytical solutions, we look for approximate ones by applying different approximation techniques like linearization, reductive perturbation, phase portraits, etc. The linear dispersion relation, obtained as a quadratic equation in the plasma frequency ω2, reveals interesting features. The small amplitude analysis for the nonlinear waves, using the reductive perturbation technique, yields the Korteweg–de Vries equation, whose solutions are solitary waves. The effects of various physical parameters like speed and angle of rotation, strength of the magnetic field, the quantum diffraction term, etc., on the shape of the nonlinear structures, are investigated numerically. It is observed that the different plasma parameters have similar effects on both small and arbitrary amplitude waves—stronger magnetic field, larger quantum effects, and higher speed of rotation decrease their width. Furthermore, as the angle between the rotation axis and magnetic axis decreases, i.e., the rotation is aligned with the direction of the magnetic field, the waves get sharper. Additionally, the energy of the small amplitude solitary wave decreases with an increase in the speed of rotation and stronger quantum effects.

Compound 3a, DV2-103, is a kinase inactive analogue of a potent Abl1/Src kinase inhibitor, PD173955, 2. Both compounds, 2 and 3a, are known to reduce production of beta amyloid (Aβ) peptide in cells and animal models. We have now prepared and evaluated a series of PD-173955 analogues, several of which reduced Aβ production potently. This occurs in cells expressing human full-length amyloid precursor protein (APP) and not in cells expressing APP β-C terminal fragment (APP-C99), suggesting that the kinase inactive analogues strongly affect β-secretase (BACE1) cleavage of APP, similarly to Gleevec. A combination of the kinase inactive analogues of PD173955 with a BACE1 inhibitor (BACEi), namely, BACE IV, strongly reduced Aβ levels in cells, as noted previously with Gleevec and analogues. Several potent compounds also penetrated and accumulated in mouse brain in high nanomolar to low micromolar concentration.

Imatinib mesylate, 1a, inhibits production of β-amyloid (Aβ) peptides both in cells and in animal models. It reduces both the β-secretase and γ-secretase cleavages of the amyloid precursor protein (APP) and mediates a synergistic effect, when combined with a β-secretase inhibitor, BACE IV. Toward developing more potent brain-permeable leads, we have synthesized and evaluated over 75 1a-analogues. Several compounds, including 2a-b and 3a-c, inhibited production of Aβ peptides with improved activity in cells. These compounds affected β-secretase cleavage of APP similarly to 1a. Compound 2a significantly reduced production of the Aβ42 peptide, when administered (100 mg/kg, twice daily by oral gavage) to 5 months old female mice for 5 days. A combination of compound 2a with BACE IV also reduced Aβ levels in cells, more than the additive effect of the two compounds. These results open a new avenue for developing treatments for Alzheimer's disease using 1a-analogues.

Nonlinear wave propagation is studied in a dissipative, self-gravitating Bose-Einstein condensate, starting from the Gross-Pitaevskii equation. In the absence of an exact analytical result, approximate methods like the linear analysis and perturbative approach are applied. The linear dispersion relation puts a restriction on the permissible range of the dissipation parameter. The waves get damped due to dissipation. The small amplitude analysis using reductive perturbation technique is found to yield a modified form of KdV equation, which is solved both analytically as well as numerically. Interestingly, the analytical and numerical plots match excellently with each other, in the realm of weak dissipation.

A theoretical study is presented for the oblique propagation of linear and nonlinear electron acoustic waves (EAWs) in a two-electron population, dissipative, quantum magnetoplasma. The linear dispersion relation yields a complex plasma wave frequency \(\omega\), denoting a decaying wave, with the amount of damping directly related to the strength of the dissipative force. The small amplitude analysis for the nonlinear structures using the reductive perturbation technique, gives the Korteweg-de Vries-Burgers equation. The numerical solutions depict a soliton for negligible dissipation and a monotonic shock for relatively large dissipation. For intermediate values, the solutions are damped oscillations. The dispersion of the EAWs gets enhanced with increase in strength of the magnetic field and a higher value of the ratio of hot to cold electron density. The stability analysis is also carried out, and the corresponding phase portraits are plotted to observe the trajectories. Of the two critical points, one is a saddle point, hence always unstable, while the other is a stable focus or a stable node, depending on the relative strengths of the plasma parameters.

Using the theoretical formalism of G E Volvik and Macro Fedi, we have studied the links between gravity and dynamics of quantum liquids. We have also outlined the gravity as a fluid dynamic phenomenon in super fluid quantum space. The detailed studies are the following: From above theoretical investigation, we have discussed effective gravity of super fluids. Quantized vortices with circulating super fluid velocity around them simulate the spinning cosmic strings. We have very elaborately discussed gravity as fluid dynamic phenomenon in a super fluid quantum space (SQS). We have outlined various examples in which quantum phenomenon resembles quantum super fluid.

Using the quantum hydrodynamical model, we study the effect of collisions on the dynamics of nonlinear ion-acoustic waves in a superdense degenerate electron-ion plasma. The electrons are assumed to be moving with relativistic velocities. The standard reductive perturbation technique leads to a dissipative KdV equation, for small amplitude electrostatic potential disturbances. The dynamics of these solitary waves is studied both analytically as well as numerically. It is observed that the system supports both positive as well as negative potential ion-solitary waves. The interplay between the relativistic degeneracy parameter and the ion-neutral collision frequency gives rise to both dispersion and dissipation, such that the soliton energy, amplitude, and velocity decrease exponentially with time, whereas its width increases.

We study the interplay between dispersion due to the electron degeneracy parameter and dissipation caused by plasma resistivity, in degenerate Fermi–Dirac Pauli quantum plasma. Considering relativistic degeneracy pressure for electrons, we investigate both arbitrary and small amplitude nonlinear structures. The corresponding trajectories are also plotted in the phase plane. The linear analysis for the dispersion relation yields interesting features. The present work is anticipated to be of physical relevance in the study of compact magnetized astrophysical objects like white dwarfs.

The shock structures in spin-1/2 quantum plasma, in the presence of magnetic diffusivity, are studied in the framework of the quantum magnetohydrodynamic model. Linear dispersion relation for the system is carried out analytically, and the results are plotted numerically for several values of the plasma parameters. Numerical analysis for arbitrary amplitude waves is carried out, whereas for waves of small amplitude, the reductive perturbation technique is applied to obtain the Korteweg-de Vries-Burgers equation. Both the analyses are observed to give the same qualitative picture. Most importantly, the different plasma parameters are found to play significant roles in determining the nature of the shock waves. The parametric ranges for which monotonic shock and oscillatory shock solutions are observed, are found analytically.

A numerical study is presented of the nonlinear dynamics of a magnetized, cold, non-relativistic plasma, in the presence of electron-ion collisions. The ions are considered to be immobile while the electrons move with non-relativistic velocities. The primary interest is to study the effects of the collision parameter, external magnetic field strength, and the initial electromagnetic polarization on the evolution of the plasma system.

In this work we study scattering in a 𝓟𝓣 symmetric periodic optical lattice, when two coherent beams are incident on it from two opposite directions. We focus our attention on both 𝓟𝓣 broken as well as 𝓟𝓣 unbroken phase, with special emphasis on spectral singularity. This is another example of an analytically solvable model, apart from the 𝓟𝓣 symmetric Scarf II potential discussed in ref. Ahmed (Phys. Rev. A 81, 022102 (2014)), which exhibits the phenomenon of Coherent Perfect Absorption (CPA) with lasing, in the domain of broken 𝓟𝓣 symmetry. At the same time, CPA is neither possible for unbroken 𝓟𝓣 symmetry, nor at the transition point.