The p53-caspase-2 axis in the cell cycle and DNA damage response

Caspase-2 was discovered almost three decades ago. It was one of the first two mammalian homologs of CED-3, the other being interleukin 1β-converting enzyme (ICE/caspase-1). Despite high similarity with CED-3 and its fly and mammalian counterparts (DRONC and caspase-9, respectively), the function of caspase-2 in apoptosis has remained enigmatic. A number of recent studies suggest that caspase-2 plays an important role in the regulation of p53 in response to cellular stress and DNA damage to prevent the proliferation and accumulation of damaged or aberrant cells. Here, we review these recent observations and their implications in caspase-2-mediated cellular death, senescence, and tumor suppression.Subject terms: Apoptosis, Experimental models of disease     

Synthesis of a pipecolic acid-based bis-amino acid and its assembly into a spiro ladder oligomer

[reaction: see text] The synthesis of a new pipecolic acid-based bis-amino acid building block 1 (and 2) is presented. Assembly of this monomer into a spiro ladder oligomer 3 utilizing solid-phase synthesis followed by in situ activation by dicyclohexylcarbodiimide and N-hydroxysuccinimide has been demonstrated. The structure of oligomer 3, determined in aqueous solution using two-dimensional NMR, reveals that the oligomer forms a left-handed helix and that each monomer unit adopts a chair conformation.     

Evaluation of the photosensitizer Tookad for photodynamic therapy on the Syrian golden hamster cheek pouch model: light dose, drug dose and drug-light interval effects

We have evaluated the efficacy of the new photosensitizer (PS) Tookad in photodynamic therapy (PDT) in vivo. This PS is a palladium-bacteriopheophorbide presenting absorption peaks at 762 and 538 nm. The light dose, drug dose and drug injection-light irradiation interval (DLI), ranging between 100 and 300 J/cm2, 1 and 5 mg/kg and from 10 to 240 min, respectively, were varied, and the response to PDT was analyzed by staging the macroscopic response and by the histological examination of the sections of the irradiated cheek pouch. The level of PDT response, macroscopically and histologically, shows a strong dependence on the DLI, light dose and drug dose at the applied conditions in the normal hamster cheek pouch. A decay of the tissular response with increasing DLI is observed corresponding to a time of half-maximum response ranging from 10 to 120 min, depending on drug dose and light dose. The tissues affected at the lowest doses are predominantly the vascularized diffuse connective tissue situated between the inner and outer striated muscle (SM) layers as well as these muscle layers themselves. The highest response at the shortest DLI and the absence of a measurable response at DLI longer than 240 min at 300 J/cm2 and drug dose of 5 mg/kg are characteristics of a predominantly vascular effect of this PS. This observation suggests that Tookad could be effective in PDT of vascularized lesions or pathologies associated with the proliferation of neovessels.     

A [2+2+2]-cyclotrimerization approach for the synthesis of enantiopure isochromans using a carbohydrate derived dialkyne template

An easy access to enantiopure isochromans through cross alkyne trimerization of a glucose derived dialkyne was developed. One of the synthesized isochromans was converted into a novel tricyclic nucleoside by simple transformations.     

Autocatalytic formation of green heme: evidence for H2O2-dependent formation of a covalent methionine-heme linkage in ascorbate peroxidase

The mammalian heme peroxidases are distinguished from their plant and fungal counterparts by the fact that the heme group is covalently bound to the protein through ester links from glutamate and aspartate residues to the heme 1- and 5-methyl groups and, in the case of myeloperoxidase, through an additional sulfonium link from the Cbeta of the 2-vinyl group to a methionine residue. To duplicate the sulfonium link in myeloperoxidase and to obtain information on its mechanism of formation, we have engineered a methionine residue close to the 2-vinyl group in recombinant pea cytosolic ascorbate peroxidase (rpAPX) by replacement of Ser160 by Met (S160M variant). The S160M variant is isolated from Escherichia coli as apo-protein. Reconstitution of apo-S160M with exogenous heme gives a red protein (S160M(R)) which has UV-visible (lambda(max)/nm = 407, 511, 633) and steady-state kinetic (kcat = 156 +/- 7 s(-1), KM = 102 +/- 15 microM) properties that are analogous to those of rpAPX. The reaction of S160M(R) with H2O2 gives a green protein (S160M(G)). Electronic spectroscopy, mass spectrometry, and HPLC analyses are consistent with the formation of a covalent linkage between the methionine residue and the heme vinyl group in S160M(G). Single-wavelength and photodiode array stopped-flow kinetic analyses identify a transient Compound I species as a reaction intermediate. The results provide the first direct evidence that covalent heme linkage formation occurs as an H2O2-dependent process that involves Compound I formation. A mechanism that is consistent with the data is presented.     

Quasi-symmetric 2, 3, 4-designs

Quasi-symmetric designs are block designs with two block intersection numbersx andy It is shown that with the exception of (x, y)=(0, 1), for a fixed value of the block sizek, there are finitely many such designs. Some finiteness results on block graphs are derived. For a quasi-symmetric 3-design with positivex andy, the intersection numbers are shown to be roots of a quadratic whose coefficients are polynomial functions ofv, k and λ. Using this quadratic, various characterizations of the Witt—Lüneburg design on 23 points are obtained. It is shown that ifx=1, then a fixed value of λ determines at most finitely many such designs.     

Dielectric characterisation of a ferroelectric liquid crystalline material having SmA*–SmC*–SmBh* phase sequence

Thermodynamical, optical and dielectric characterisation of a material possessing ferroelectric SmC* and hexatic SmB* phases has been carried out. Phase identification has been done by miscibility studies. From the dielectric studies, a relaxation mechanism is observed in the low MHz region of the SmA* phase, which is related to the tilt fluctuation (soft mode) of the directors. In the SmC* phase, another collective relaxation mechanism has been observed in the kHz region, which is related to the phase fluctuation (Goldstone mode) of the directors. In the SmB_h* phase, 2-weak relaxation modes are observed in the kHz and MHz frequency range, respectively, due to individual molecular rotations.     

UDCaT‐5: A Novel and Efficient Solid Superacid Catalyst for Claisen Rearrangement of Substituted Allyl Phenyl Ethers

The Claisen rearrangement of allyl phenyl ethers is a fundamental reaction in organic synthesis with a variety of applications in perfumes, flavors, pharmaceuticals, agrochemicals, polymers, fine chemicals, and intermediate industries. The development of environmentally benign processes using solid acid catalysts is becoming an area of growing interest. It was accomplished in an efficient, economical, environmentally friendly manner and is 100% selective toward alllyl phenols by employing UDCaT‐5 as solid acid catalyst.