57 research outputs found
Understanding the nature of "superhard graphite"
Numerous experiments showed that on cold compression graphite transforms into
a new superhard and transparent allotrope. Several structures with different
topologies have been proposed for this phase. While experimental data are
consistent with these models, the only way to solve this puzzle is to find
which structure is kinetically easiest to form. Using state-of-the-art
molecular-dynamics transition path sampling simulations, we investigate kinetic
pathways of the pressure-induced transformation of graphite to various
superhard candidate structures. Unlike hitherto applied methods for elucidating
nature of superhard graphite, transition path sampling realistically models
nucleation events necessary for physically meaningful transformation kinetics.
We demonstrate that nucleation mechanism and kinetics lead to -carbon as the
final product. -carbon, initially competitor to -carbon, is ruled out by
phase growth. Bct-C structure is not expected to be produced by cold
compression due to less probable nucleation and higher barrier of formation
Variable Nav1.5 Protein Expression from the Wild-Type Allele Correlates with the Penetrance of Cardiac Conduction Disease in the Scn5a+/− Mouse Model
BACKGROUND: Loss-of-function mutations in SCN5A, the gene encoding Na(v)1.5 Na+ channel, are associated with inherited cardiac conduction defects and Brugada syndrome, which both exhibit variable phenotypic penetrance of conduction defects. We investigated the mechanisms of this heterogeneity in a mouse model with heterozygous targeted disruption of Scn5a (Scn5a(+/-) mice) and compared our results to those obtained in patients with loss-of-function mutations in SCN5A. METHODOLOGY/PRINCIPAL FINDINGS: Based on ECG, 10-week-old Scn5a(+/-) mice were divided into 2 subgroups, one displaying severe ventricular conduction defects (QRS interval>18 ms) and one a mild phenotype (QRS53 weeks), ajmaline effect was larger in the severely affected subgroup. These data matched the clinical observations on patients with SCN5A loss-of-function mutations with either severe or mild conduction defects. Ventricular tachycardia developed in 5/10 old severely affected Scn5a(+/-) mice but not in mildly affected ones. Correspondingly, symptomatic SCN5A-mutated Brugada patients had more severe conduction defects than asymptomatic patients. Old severely affected Scn5a(+/-) mice but not mildly affected ones showed extensive cardiac fibrosis. Mildly affected Scn5a(+/-) mice had similar Na(v)1.5 mRNA but higher Na(v)1.5 protein expression, and moderately larger I(Na) current than severely affected Scn5a(+/-) mice. As a consequence, action potential upstroke velocity was more decreased in severely affected Scn5a(+/-) mice than in mildly affected ones. CONCLUSIONS: Scn5a(+/-) mice show similar phenotypic heterogeneity as SCN5A-mutated patients. In Scn5a(+/-) mice, phenotype severity correlates with wild-type Na(v)1.5 protein expression
Novel antitenascin antibody with increased tumour localisation for Pretargeted Antibody-Guided RadioImmunoTherapy (PAGRITR)
Back to the Future: A Review and Editorial Agenda of the International Journal of Business Research and Management
SYNTHESIS AND CYTOTOXICITY OF DNA-INTERACTIVE PYRROLO[2,1-C][1,4]BENZODIAZEPINONE HETEROCYCLIC-ANALOGS
The pyrrolo[2,1-C][1,4]benzodizepines (PBDs) are a family of sequence-selective DNA-binding anti tumor antibiotics that bind exclusively to the exocyclic N2 of guanine in the minor groove of DNA. Footprinting-type studies have shown that the adduct span 3 base-pairs with a rank order of preference for 5'-Pu-G-Pu>5'->Pu-G-Py or 5'-Py-G-Pu>5'-Py-G-Py sequences. In a project aimed to design new analogues lacking both cardiotoxicity and tissue necrosis, we have substituted theA benzene ring of the PBD skeleton with different heterocycle nucleus such as substituted pyrazoles, pyridine and pyrimidine. The rationale behind the synthesis of the heterocyclic analogues reported here has been to design molecules with the following features:i)a possibly higher binding affinity and modified sequence selectivity for the DNAminor groove, due to the potential new hydrogen bonds that might occur between the A-ring atoms and DNA bases;ii)a reduced cardiotoxicity due to the impossibility of C9-quinone formation as occurs with anthramycin. The synthesized compounds were evaluated for cytotoxicity by growth inhibition studies in L1210 murine leukemia and its L1210/L-PAM sublime cells resistant to melphalan (L-PAM) and LoVo human coloncarcinoma and its sublime (LoVo/DX) resistant to Doxorubicin(DX). Among the most cytotoxic compounds containing the pyrazole ring it is interesting to note that:1)substitution at N7 increases cytotoxicity with respect to the N6 substituted compounds in L1210 and L1210/L-PAM cell lines;2)the N7 benzyl or N7 substituted benzyl compounds are similar or superior to N7 methyl or ethyl substituted compounds in terms of cytotoxicity; 3)with the same substituent at N6 replacement of the C8 methyl group with a carboxy methyl ester does not increase cytotoxicity.4)in the L1210 cell line, the introduction of a sterically demanding substituent at C8leads to a decrease in citotoxicity compared to the C8-methyl compound
Idiotypic replica of an anti-human tumor-associated antigen monoclonal antibody. Analysis of monoclonal Ab1 and Ab3 fine specificity
CaMBr1 is a tissue-specific and tumor-associated saccharidic epitope, defined by mAb MBr1 (Ab1), expressed on glycoconjugates of the human mammary carcinoma cell line MCF-7 and of normal and neoplastic mammary epithelial cells. An anti-anti-idiotypic monoclonal Ab3, 2G-3, identifying a human breast tumor associated antigen, was raised by using as immunogen a mouse anti-idiotypic monoclonal Ab2, A3B10, which behaves as the internal image of CaMBr1. mAb 2G-3, as well as MBr1, defines a saccharidic epitope on glycoconjugates extracted from MCF-7 cells and shows MBr1-like reactivity on normal and neoplastic-tissues. Experimental evidence, however, suggests that the fine immunoreactivity of the two antibodies is not identical, because MBr1 has a preferential reactivity with glycolipids and 2G-3 with glycoproteins. We suggest that a possible biologic explanation for our findings could reside in the nature of the immunogens used to raise the two mAb (glycolipid vs protein 'internal image')
Synthesis, antibacterial activity and structure-activity relationships of N-substituted 4-diazo-pyrazole-5-carboxamides
A series of 4-diazopyrazole-5-carboxamides 1 d-n has been synthesized and their antibacterial activity against a number of Gram-negative and Gram-positive strains has been tested. Some of the compounds resulted quite active and the whole set allowed to further study the SAR of the class. Substituents in position 5 affect Gram-negative and Gram-positive activities via bulk and electronic properties respectively; position 3 mostly affects the Gram-negative activity, while the presence of the charged diazo group in position 4 is crucial for both antibacterial activities
Effect of A-ring modifications on the DNA-binding behavior and cytotoxicity of pyrrolo[2,1-c][1,4]benzodiazepines.
Several A-ring-modified analogues of the DNA-binding antitumor agent DC-81 (5) have been synthesized in order to study structure−reactivity/cytotoxicity relationships. For two molecules (23 and 30) the modifications required the addition of a fourth ring to give the novel dioxolo[4,5-h]- and dioxano[5,6-h]pyrrolo[2,1-c][1,4]benzodiazepin-11-one (PBD) ring systems, respectively. Another three analogues (34, 38, and 48) have the native benzenoid A-ring replaced with pyridine, diazine, or pyrimidine rings to give the novel pyrrolo[2,1-c][1,4]pyridodiazepine, pyrrolo[2,1-c][1,4]diazinodiazepine, and pyrrolo[2,1-c][1,4]pyrimidinodiazepine systems, respectively. The other new analogues (16a,b) have extended chains at the C8-position of the DC-81 structure. During the synthesis of these compounds, a novel tin-mediated regiospecific cleavage reaction of the dioxole intermediate 18 was discovered, leading to the previously unknown iso-DC-81 (20). In addition, an unusual simultaneous nitration−oxidation reaction of 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (8) was found to produce 3-(4-carboxy-2-methoxy-5-nitrophenoxy)propanoic acid (9), a key intermediate, in high yield. In general, the results of cytotoxicity and DNA-binding studies indicated that none of the changes made to the A-ring of the PBD system significantly improved either binding affinity or cytotoxicity in comparison to DC-81. This result suggests that the superior potency of natural products such as anthramycin (1), tomaymycin (2), and sibiromycin (3) is due entirely to differences in C-ring structure, and in particular exo or endo unsaturation at the C2-position and C2-substituents containing unsaturation. This study also provided information regarding the influence of A-ring substitution pattern on the relative stability of the interconvertible N10−C11 carbinolamine, carbinolamine methyl ether, and imine forms of PBDs
Bendamustine, pomalidomide, and dexamethasone for relapsed and/or refractory multiple myeloma
- …