Akt activation ameliorates deficits in hippocampal-dependent memory and activity-dependent synaptic protein synthesis in an Alzheimer's disease mouse model.

Protein kinase-B (Akt) and the mechanistic target of rapamycin (mTOR) signaling pathways are implicated in Alzheimer's disease (AD) pathology. Akt/mTOR signaling pathways, activated by external inputs, enable new protein synthesis at the synapse and synaptic plasticity. The molecular mechanisms impeding new protein synthesis at the synapse in AD pathogenesis remain elusive. Here, we aimed to understand the molecular mechanisms prior to the manifestation of histopathological hallmarks by characterizing Akt1/mTOR signaling cascades and new protein synthesis in the hippocampus of WT and amyloid precursor protein/presenilin-1 (APP/PS1) male mice. Intriguingly, compared to those in WT mice, we found significant decreases in pAkt1, pGSK3ß, pmTOR, pS6 ribosomal protein, and p4E-BP1 levels in both post nuclear supernatant and synaptosomes isolated from the hippocampus of one-month-old (presymptomatic) APP/PS1 mice. In synaptoneurosomes prepared from the hippocampus of presymptomatic APP/PS1 mice, activity-dependent protein synthesis at the synapse was impaired and this deficit was sustained in young adults. In hippocampal neurons from C57BL/6 mice, downregulation of Akt1 precluded synaptic activity-dependent protein synthesis at the dendrites but not in the soma. In three-month-old APP/PS1 mice, Akt activator (SC79) administration restored deficits in memory recall and activity-dependent synaptic protein synthesis. C57BL/6 mice administered with an Akt inhibitor (MK2206) resulted in memory recall deficits compared to those treated with vehicle. We conclude that dysregulation of Akt1/mTOR and its downstream signaling molecules in the hippocampus contribute to memory recall deficits and loss of activity-dependent synaptic protein synthesis. In AD mice, however, Akt activation ameliorates deficits in memory recall and activity-dependent synaptic protein synthesis.

Nonamer dependent RAG cleavage at CpGs can explain mechanism of chromosomal translocations associated to lymphoid cancers.

Chromosomal translocations are considered as one of the major causes of lymphoid cancers. RAG complex, which is responsible for V(D)J recombination, can also cleave non-B DNA structures and cryptic RSSs in the genome leading to chromosomal translocations. The mechanism and factors regulating the illegitimate function of RAGs resulting in oncogenesis are largely unknown. Upon in silico analysis of 3760 chromosomal translocations from lymphoid cancer patients, we find that 93% of the translocation breakpoints possess adjacent cryptic nonamers (RAG binding sequences), of which 77% had CpGs in proximity. As a proof of principle, we show that RAGs can efficiently bind to cryptic nonamers present at multiple fragile regions and cleave at adjacent mismatches generated to mimic the deamination of CpGs. ChIP studies reveal that RAGs can indeed recognize these fragile sites on a chromatin context inside the cell. Finally, we show that AID, the cytidine deaminase, plays a significant role during the generation of mismatches at CpGs and reconstitute the process of RAG-dependent generation of DNA breaks both in vitro and inside the cells. Thus, we propose a novel mechanism for generation of chromosomal translocation, where RAGs bind to the cryptic nonamer sequences and direct cleavage at adjacent mismatch generated due to deamination of meCpGs or cytosines.

Palladium-Catalyzed Synthesis of 1-Vinyltetrahydro-ß-carbolines and Aza-spiroindolenines: Access to the Syntheses of 1-Vinyl-ß-carbolines and Eudistomins Y1 and Y2.

A general synthesis of 1-vinyltetrahydro-ß-carbolines (THBCs) has been achieved via palladium(0)-catalyzed cyclocondensation between allenyltryptamines and aryl iodides. Aza-spiroindolenines could also be accessed from the N-unsubstituted indole substrates by simply tweaking the reaction conditions. DDQ-mediated oxidation of THBCs easily afforded ß-carbolines, which could be synthetically transformed into 1-aroyl-ß-carbolines of pharmacological interest. Formal total syntheses of eudistomins Y1 and Y2 have also been achieved.

Palladium-catalysed stereoselective synthesis of 4-(diarylmethylidene)-3,4-dihydroisoquinolin-1(2H)-ones: expedient access to 4-substituted isoquinolin-1(2H)-ones and isoquinolines.

An efficient method has been developed for the stereoselective synthesis of 4-(diarylmethylidene)-3,4-dihydroisoquinolin-1(2H)-ones 7 through tandem Heck-Suzuki coupling at rt using easily available substrates. DBU easily converted the exocyclic double bond of these compounds to endo, furnishing 8 and 9. Reduction of the carbonyl group of 7 was smoothly carried out with borane dimethyl sulphide. Subsequent treatment with KOtBu provided an easy access to 4-substituted isoquinolines 10a if carried out in refluxing 1,4-dioxane, while reaction in DMF at rt led to the incorporation of an extra hydroxyl group at the benzylic position of the isoquinolines to give 10b. This straightforward and metal free procedure would serve as a better alternative to the prevalent procedures. Few of the products could also be transformed into heterocyclic scaffolds structurally resembling known bioactive compounds.

A Palladium-Catalyzed Method for the Synthesis of 2-(α-Styryl)-2,3-dihydroquinazolin-4-ones and 3-(α-Styryl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: Access to 2-(α-Styryl)quinazolin-4(3H)-ones and 3-(α-Styryl)-1,2,4-benzothiadiazine-1,1-dioxides.

An efficient synthesis of 2-(α-styryl)-2,3-dihydroquinazolin-4-ones and 3-(α-styryl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides has been achieved in 39-94% yield through palladium-catalyzed cyclocondensation of aryl/vinyl iodides with allenamides 13-15 and 22, respectively. Base treatment of the N-tosylated products provides an easy access to 2-(α-styryl)quinazolin-4(3H)-ones and 3-(α-styryl)-1,2,4-benzothiadiazine-1,1-dioxides, hitherto unknown heterocycles. The method has been tested with phenyl substituted allenamides, applied for bis-heteroannulation, and used in the preparation of analogues of the natural product Luotonin F.

Unlocking the Potential of Induced Pluripotent Stem Cells in Revolutionizing Cancer Therapy.

Induced Pluripotent Stem Cells (iPSCs) are among the top versatile implements of biomedical research. Stem cell science has made strides over the past few years, emerging as a new opportunity to treat cancer, and many such continuous initiatives have been made into clinical trials. As the global mortality rate is too high despite the effectiveness of prevalent cancer therapies, this review explores the potential of iPSC in different aspects of cancer-related areas. The preparation of iPSCs, including their derivation from cancer stem cells, was covered after establishing the intricacy of current cancer treatments. This article highlights the potential of iPSC- based NK cells and dendritic cells for immunotherapy and delves into the role of iPSC-based mesenchymal cells in targeted therapy. The potential of iPSC-derived organoids as a vital tool for disease modeling and drug discovery has been showcased, and the importance of iPSC-based cancer vaccines is also emphasized. The ongoing clinical trials of iPSC-based cancer treatment have also been highlighted. Though much work remains to be done to implicate these iPSC-based therapeutic options from research labs to clinics and hospitals, ongoing studies and clinical/translational follow-ups raise hope for novel cancer therapies employing iPSC technology.

Interactions and Dynamics in Aqueous Solutions of pH-Responsive Polymers: A Combined Fluorescence and Dielectric Relaxation Study.

Interaction and dynamics of aqueous solutions of pH-responsive smart polymers are investigated via steady-state, time-resolved fluorescence emission spectroscopy with the help of external local reporter coumarin 153 (C153), while MHz to GHz dielectric relaxation spectroscopic (DRS) measurement reports the intrinsic medium relaxation features. A series of pH-responsive random copolymers (DPL-DP60) comprising of a pH-responsive moiety 2-((leucinyl)oxy)ethyl methacrylate (l-Leu-HEMA) and hydrophobic methyl methacrylate (MMA) are synthesized and characterized. A balance between the pH-responsive (l-Leu-HEMA) and the hydrophobic (MMA) content dictates the phase transition pH, which is found to be ∼5-7 for these aqueous copolymer solutions (1 mg/mL). Dynamic light scattering measurements in aqueous solutions of these polymers reflect a small particle size (∼2-8 nm) at solution pH below their individual phase transition pH, while a large particle size (∼140-340 nm) forms beyond their phase transition pH. No signature of a phase transition pH-driven abrupt change in static and dynamic properties of aqueous polymer solutions has been registered from pH-dependent dielectric relaxation as well as solute (C153)-centric fluorescence measurements. A significant impact of varying the l-Leu-HEMA/MMA segment ratio on steady-state fluorescence emission and rotational anisotropy decay of the fluorophore solute (C153) has been observed. MHz to GHz DRS in aqueous solutions of these pH-responsive polymers reflects bulk water-like dielectric features.

Competing magnetic interactions in a dinuclear Ni(II) complex: antiferromagnetic O-H...O moiety and ferromagnetic N3- ligand.

Synthesis, structural characteristics, magnetic studies and DFT calculations in Ni(II) dinuclear complexes containing two bridging N3- and an O-H...O linkage reveal the existence of ferromagnetic interactions between Ni(II) centers via N3- ligands and antiferromagnetic interactions through the H-bonded moiety. The overall magnetic behavior of the system depends on the delicate balance between these two competing interactions.

Redox-noninnocence of N,N'-bis(6-methyl-2-pyridylmethylene)ethane-1,2-diamine (L): synthesis and characterization of diamagnetic [Ni(II)2(L**)2] and [Zn(II)2(L)Cl4]((L**)2- pi diradical dianion of L).

The synthesis of two diamagnetic dinuclear complexes [Ni(II)2(L**)2] (1) and [Zn(II)2(L)Cl4] (2) and an octahedral, paramagnetic, mononuclear complex [Fe(II)(L)Cl2] (3) (S = 2) is reported; the tetradentate ligand N,N'-bis(6-methyl-2-pyridylmethylene)ethane-1,2-diamine, L, is shown to be redox noninnocent. It exists in its neutral closed-shell form L in 2 and 3 and in its dianionic diradical form, (L**)2-, in 1.

Family of mixed-valence oxovanadium(IV/V) dinuclear entities incorporating N4O3-coordinating heptadentate ligands: synthesis, structure, and EPR spectra.

Dinuclear (V(IV)V(V)) oxophenoxovanadates of general formula [V2O3L] have been synthesized in excellent yields by reacting bis(acetylacetonato)oxovanadium(IV) with H3L in a 2:1 ratio in acetone under an N2 atmosphere. Here L3- is the deprotonated form of 2,6-bis[{{(2-hydroxybenzyl)(N',N'-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol (H3L1), 2,6-bis[{{(5-methyl-2-hydroxybenzyl)(N',N'-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol (H3L2), 2,6-bis[{{(5-tert-butyl-2-hydroxybenzyl)(N',N'-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol (H3L3), 2,6-bis[{{(5-chloro-2-hydroxybenzyl)(N',N'-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol(H3L4), 2,6-bis[{{(5-bromo-2-hydroxybenzyl)(N'N'-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol (H3L5), or 2,6-bis[{{(5-methoxy-2-hydroxybenzyl)(N'N'-(dimethylamino)ethyl)}methyl]-4-methylphenol (H3L6). In [V2O3L1], both the metal atoms have distorted octahedral geometry. The relative disposition of two terminal V=O groups in the complex is essentially cis. The O=V...V=O torsion angle is 24.6(2) degrees . The V-O(oxo)-V and V-O(phenoxo)-V angles are 117.5(4) and 93.4(3) degrees , respectively. The V...V bond distance is 3.173(5) A. X-ray crystallography, IR, UV-vis, and 1H and 51V NMR measurements show that the mixed-valence complexes contain two indistinguishable vanadium atoms (type III). The thermal ellipsoids of O2, O4, C10, C14, and C15 also suggests a type III complex in the solid state. EPR spectra of solid complexes at 77 K display a single line indicating the localization of the odd electron (3d(xy)1). Valence localization at 77 K is also consistent with the 51V hyperfine structure of the axial EPR spectra (3d(xy)1 ground state) of the complexes in frozen (77 K) dichloromethane solution: S = 1/2, g(parallel) approximately 1.94, g(perpendicular) approximately 1.98, A(parallel) approximately 166 x 10(-4) cm(-1), and A(perpendicular) approximately 68 x 10(-4) cm(-1). In contrast isotropic room-temperature solution spectra of the family have 15 hyperfine lines (g(iso) approximately 1.974 and A(iso) approximately 50 x 10(-4) cm(-1)) revealing that the unpaired electron is delocalized between the metal centers. Crystal data for the [V2O3L1].CH2Cl2 complex are as follows: chemical formula, C32H43O6N4Cl2V2; crystal system, monoclinic; space group, C2/c; a = 18.461(4), b = 17.230(3), c = 13.700(3) A; beta = 117.88(3) degrees ; Z = 8.

A family of oxorhenium(v) complexes incorporating chelated monoanionic ONN reduced Schiff base and dianionic ONNO tetradentate ligands: synthesis, spectroscopic and electrochemical studies.

The green colored complexes of the type Re(V)O(L(SB))Cl(2), 1, have been synthesised by reacting NBu(4)[ReOCl(4)] with HL(SB) in dry ethanol. Here, L(SB)(-) are the deprotonated forms of N-(2-hydroxybenzyl)-2-picolylamine (HL(SB)(1)); N-(2-hydroxybenzyl)-N',N'-dimethylethylenediamine (HL(SB)(2)) and N-(2-hydroxybenzyl)-N',N'-diethylethylenediamine (HL(SB)(3)). Similarly, NBu(4)[ReOCl(4)] reacted with N,N-bis(2-hydroxybenzyl)-2-picolylamine (H(2)L(1)); N,N-bis(2-hydroxybenzyl)-N',N'-dimethylethylenediamine (H(2)L(2)); N,N-bis(2-hydroxybenzyl)-N',N'-diethylethylenediamine (H(2)L(3)); [N-(2-hydroxybenzyl)-N-(2-pyridylmethyl)]-2-aminoethanol (H(2)L(4)); [N-(2-hydroxybenzyl)-N-(2-pyridylmethyl)]-2-methyl-2-amino-1-propanol (H(2)L(5)); N,N-bis(1-hydroxyethyl)-2-picolylamine (H(2)L(6)), to give the monochloro complexes Re(V)O(L)Cl, 2. The X-ray structures of the complexes are reported. The molecular structures observed in the solid state are preserved in solution ((1)H NMR). In acetonitrile solution the Re(V)O(L)Cl, 2, display a one-electron couple, Re(VI)O(L)Cl(+)-Re(V)O(L)Cl, near 1.0 V vs SCE. The electrogenerated hexavalent complexes [Re(VI)O(L)Cl]ClO(4), 3, are paramagnetic and display sextet EPR spectra in solution at room temperature (A(av) approximately 417 (G), g approximately 1.914).