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PubMed2005

The functional layered organosilica materials prepared with anion surfactant templates.

A novel strategy for the synthesis of layered organosilica is demonstrated. The ionic interaction between the anionic group of a surfactant (sodium dodecyl sulfate) and the cationic organic group of an organosilane (3-aminopropyltrimethoxysilane, ATMS) under acidic conditions was utilized to create a layered organosilica at room temperature. The inorganic part of the organosilica layer was an Si-O hexagonal sheet, and organofunctional groups were alternately arranged on both sides of the sheet. The layered structure of the ATMS organosilica was retained after the removal of the surfactant with chloride anion. The properties of the layered ATMS organosilica were investigated. The layered ATMS-Cl organosilica is stable and possesses a definite layer structure in water or ethanol. Various kinds of anions can be intercalated in the interlayer space of the layered ATMS organosilicas and the layer was expanded dependent on the intercalated anions. The structure of the layered ATMS organosilica was well retained during the intercalation processes.

Journal Article↗
PubMed2006

Regulation of radiation-induced protein kinase Cdelta activation in radiation-induced apoptosis differs between radiosensitive and radioresistant mouse thymic lymphoma cell lines.

Protein kinase Cdelta (PKCdelta) has an important role in radiation-induced apoptosis. The expression and function of PKCdelta in radiation-induced apoptosis were assessed in a radiation-sensitive mouse thymic lymphoma cell line, 3SBH5, and its radioresistant variant, XR223. Rottlerin, a PKCdelta-specific inhibitor, completely abolished radiation-induced apoptosis in 3SBH5. Radiation-induced PKCdelta activation correlated with the degradation of PKCdelta, indicating that PKCdelta activation through degradation is involved in radiation-induced apoptosis in radiosensitive 3SBH5. In radioresistant XR223, radiation-induced PKCdelta activation was lower than that in radiosensitive 3SBH5. Cytosol PKCdelta levels in 3SBH5 decreased markedly after irradiation, while those in XR223 did not. There was no apparent change after irradiation in the membrane fractions of either cell type. In addition, basal cytosol PKCdelta levels in XR223 were higher than those in 3SBH5. These results suggest that the radioresistance in XR223 to radiation-induced apoptosis is due to a difference in the regulation of radiation-induced PKCdelta activation compared to that of 3SBH5. On the other hand, Atm(-/-) mouse thymic lymphoma cells were more radioresistant to radiation-induced apoptosis than wild-type mouse thymic lymphoma cells. Irradiated wild-type cells, but not Atm(-/-) cells, had decreased PKCdelta levels, indicating that the Atm protein is involved in radiation-induced apoptosis through the induction of PKCdelta degradation. The decreased Atm protein levels induced by treatment with Atm small interfering RNA had no effect on radiation-induced apoptosis in 3SBH5 cells. These results suggest that the regulation of radiation-induced PKCdelta activation, which is distinct from the Atm-mediated cascade, determines radiation sensitivity in radiosensitive 3SBH5 cells.

Acetophenones↗
PubMed1969

A study of the effects of hydrostatic pressure on macromolecular synthesis in Escherichia coli.

In cultures of Escherichia coli 15 (thymine(-), leucine(-)) which were incubated at high hydrostatic pressures, cell division occurred only at pressures below 430 atm but in a somewhat synchronous fashion at around 250 atm. The rate of leucine-(14)C incorporation into a macromolecular fraction of the cells diminished to a zero value at about 580 atm and that of uracil-(14)C incorporation to a zero value at about 770 atm. The rate of thymine-(14)C incorporation at pressures around 330 atm was that to be expected with a culture in which DNA synthesis is somewhat synchronous. At pressures above 500 atm, thymine-(14)C was incorporated only over the initial part of the pressure incubation and further incorporation under pressure was not observed no matter how long the duration of the incubation. We present evidence along several lines that the thymine incorporation kinetics reflect an effect of pressure on a locus at the origin (or termination) of a replication of the bacterial chromosome. The recovery of cell division and of the incorporation rates upon release of pressure were found to depend on the magnitude of the pressure and the duration of the pressure incubation.

Bacterial Proteins↗
PubMed2001

Radiation induced apoptosis in ataxia telangiectasia homozygote, heterozygote and normal cells.

Recent reports suggest that the radiation-induced, p53-dependent, apoptotic response is aberrant in ataxia telangiectasia (AT) cells. We investigated the possibility that an aberrant apoptotic response to ionizing radiation may also be the characteristic of AT heterozygotes and may facilitate in discriminating AT heterozygotes from the general population. Log phase, Epstein Barr virus (EBV) transformed lymphoblastoid cell lines and primary lymphocytes from three AT families were irradiated and the apoptotic response at 30h post radiation was measured by flow cytometry using TUNEL and hypodiploid methods. Our results show that the apoptotic response of AT homozygote (ATM-/-), AT heterozygote (ATM+/-) and normal cells (ATM+/+) to ionizing radiation, measured by the hypodiploid and TUNEL methods using flow cytometry, is dose and time dependent. Furthermore, this response is paradoxical in that ATM (-/-) lymphoblastoid cells were characterized by a reduced post radiation apoptotic response compared to their normal counterparts. Heterozygote (ATM+/-) lymphoblastoid cells displayed an intermediate response to ionizing radiation. In contrast, primary, non-transformed AT cells exhibited the same apoptotic response as their normal counterparts. Our results thus indicate that pre-radiation, EBV-transformed, lymphoblastoid cell lines from individual families may be useful in discriminating ATM status, but patient-derived, primary AT homozygous, heterozygous and normal primary cultured lymphocytes cannot be discriminated by this assay.

Apoptosis↗
PubMed1996

Ditungsten Siloxide Hydrides, [(silox)(2)WH(n)()](2) (n = 1, 2; silox = (t)BuSiO), and Related Complexes.

The addition of 4.0 equiv of Na(silox) to Na[W(2)Cl(7)(THF)(5)] afforded (silox)(2)ClW&tbd1;WCl(silox)(2) (1, 65%). Treatment of 1 with 2.0 equiv of MeMgBr in Et(2)O provided (silox)(2)MeW&tbd1;WMe(silox)(2) (2, 81%). In the presence of 1 atm of H(2), reduction of 1 with 2.0 equiv of Na/Hg in DME provided (silox)(2)HW&tbd1;WH(silox)(2) (3, 70%), characterized by a hydride resonance at delta 19.69 (J(WH) = 325 Hz, (1)H NMR). Exposure of 2 to 1 atm of H(2) yielded 3 and CH(4) via (silox)(2)HW&tbd1;WMe(silox)(2) (4); use of D(2) led to [(silox)(2)WD](2) (3-d(2)). Exposure of 3 to ethylene ( approximately 1 atm, 25 degrees C) in hexanes generated (silox)(2)EtW&tbd1;WEt(silox)(2) (5), but solutions of 5 reverted to 3 and free C(2)H(4) upon standing. NMR spectral data are consistent with a sterically locked, gauche, C(2) symmetry for 1-5. Thermolysis of 3 at 100 degrees C (4 h) resulted in partial conversion to (silox)(2)HW&tbd1;W(OSi(t)Bu(2)CMe(2)CH(2))(silox) (6a, approximately 60%) and free H(2), while extended thermolysis with degassing (5 d, 70 degrees C) produced a second cyclometalated rotational isomer, 6b (6a:6b approximately 3:1). When left at 25 degrees C (4 h) in sealed NMR tubes, 6 and free H(2) regenerated 3. Reduction of 1 with 2.0 equiv of Na/Hg in DME also afforded 6a (25%). When 3 was exposed to approximately 3 atm of H(2), equilibrium amounts of [(silox)(2)WH(2)](2) (7) were observed by (1)H NMR spectroscopy (3 + H(2) right harpoon over left harpoon 7; 25.9-88.7 degrees C, DeltaH = -9.6(4) kcal/mol, DeltaS = -21(2) eu). Benzene solutions of 3 and 1-3 atm of D(2) revealed incorporation of deuterium into the silox ligands, presumably via intermediate 6. In sealed tubes containing [(silox)(2)WCl](2) (1) and dihydrogen (1-3 atm), (1)H NMR spectral evidence for [(silox)(2)WCl](2)(&mgr;-H)(2) (8) was obtained, suggesting that formation of 3 from 1 proceeded via reduction of 8. Alternatively, 3 may be formed from direct reduction of 1 to give [(silox)(2)W](2) (9), followed by H(2) addition. Hydride chemical shifts for 7 are temperature dependent, varying from delta 1.39 (-70 degrees C, toluene-d(8)), to delta 3.68 (90 degrees C). (29)Si{(1)H} NMR spectra revealed a similar temperature dependence of the silox (delta 12.43, -60 degrees C, to delta 13.64, 45 degrees C) resonances. These effects may arise from thermal population of a low-lying, deltadelta, paramagnetic excited state of D(2)(d)() [(silox)(2)W](2)(&mgr;-H)(4) (DeltaE approximately 2.1 kcal/mol, chi(7a) approximately 0.03), an explanation favored over thermal equilibration with an energetically similar but structurally distinct isomer (e.g., [(silox)(2)WH(2)](2)(&mgr;-H)(2), DeltaG degrees approximately 0.69 kcal/mol, chi(7b) approximately 0.25) on the basis of spectral arguments. Extended Hückel and ab initio molecular orbital calculations on model complexes [(H(3)SiO)(2)W](2)(&mgr;-H)(4) (staggered bridged 7a', EHMO), [(H(3)SiO)(2)WH(2)](2) (all-terminal 7b', EHMO), [(H(3)SiO)(2)W](2) (9', EHMO), (HO)(4)W(2)(H(4)) (staggered-bridged 7", ab initio), and (HO)(4)W(2)(H(4)) (bent-terminal 7, ab initio) generally support the explanation of a thermally accessible excited state and assign 7 a geometry intermediate between the all-terminal and staggered-bridged forms.

Journal Article↗
PubMed2001

Antagonism of free-radical-induced damage of adlay seed and its antiproliferative effect in human histolytic lymphoma U937 monocytic cells.

The goal of our current research was to investigate the antioxidative effects of methanolic extracts from different parts of adlay seed and their antiproliferative activity in malignant human cells. The methanolic extracts from different parts of adlay seeds were from the hull (AHM), testa (ATM), bran (ABM), and polished adlay (PAM). AHM exhibited greater capacity to scavenge superoxide anion radicals in the PMS-NADH system than ATM, ABM, or PAM. The scavenging capacities of AHM and ATM on hydrogen peroxides were about 20% at a dose of 250 microg/mL. Using the method of deoxyribose degradation to assess damage caused by hydroxyl radicals, AHM was found to inhibit damage in deoxyribose at a higher concentration. However, ATM, ABM, and PAM exhibited prooxidative activity at the same concentration. The inhibitory effect on enzymatic oxidation of xanthine to uric acid was found to follow the order AHM > ATM =. ABM. However, PAM was inactive. All test samples were positive for inhibition of TPA-induced free radical formation on neutrophil-like leukocytes and were found to follow the order AHM > ATM > ABM > PAM. When human histolytic lymphoma U937 monocytic cells were exposed to tert-butyl hydroperoxide, AHM protected the cells against the cytotoxicity caused by tert-butyl hydroperoxide. In addition, AHM exhibited antiproliferative activity against human histolytic lymphoma U937 monocytic cells in a dose-dependent manner. The antiproliferative properties of AHM appear to be attributable to its induction of apoptotic cell death as determined by flow cytometry. These results show that AHM displays multiple antioxidant effects and induces apoptosis of malignant human cells.

Antineoplastic Agents↗
PubMed2006

Small molecule-based reversible reprogramming of cellular lifespan.

Most somatic cells encounter an inevitable destiny, senescence. Little progress has been made in identifying small molecules that extend the finite lifespan of normal human cells. Here we show that the intrinsic 'senescence clock' can be reset in a reversible manner by selective modulation of the ataxia telangiectasia-mutated (ATM) protein and ATM- and Rad3-related (ATR) protein with a small molecule, CGK733. This compound was identified by a high-throughput phenotypic screen with automated imaging. Employing a magnetic nanoprobe technology, magnetism-based interaction capture (MAGIC), we identified ATM as the molecular target of CGK733 from a genome-wide screen. CGK733 inhibits ATM and ATR kinase activities and blocks their checkpoint signaling pathways with great selectivity. Consistently, siRNA-mediated knockdown of ATM and ATR induced the proliferation of senescent cells, although with lesser efficiency than CGK733. These results might reflect the specific targeting of the kinase activities of ATM and ATR by CGK733 without affecting any other domains required for cell proliferation.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2002

The mismatch repair system is required for S-phase checkpoint activation.

Defective S-phase checkpoint activation results in an inability to downregulate DNA replication following genotoxic insult such as exposure to ionizing radiation. This 'radioresistant DNA synthesis' (RDS) is a phenotypic hallmark of ataxia-telangiectasia, a cancer-prone disorder caused by mutations in ATM. The mismatch repair system principally corrects nucleotide mismatches that arise during replication. Here we show that the mismatch repair system is required for activation of the S-phase checkpoint in response to ionizing radiation. Cells deficient in mismatch repair proteins showed RDS, and restoration of mismatch repair function restored normal S-phase checkpoint function. Catalytic activation of ATM and ATM-mediated phosphorylation of the protein NBS1 (also called nibrin) occurred independently of mismatch repair. However, ATM-dependent phosphorylation and activation of the checkpoint kinase CHK2 and subsequent degradation of its downstream target, CDC25A, was abrogated in cells lacking mismatch repair. In vitro and in vivo approaches both show that MSH2 binds to CHK2 and that MLH1 associates with ATM. These findings indicate that the mismatch repair complex formed at the sites of DNA damage facilitates the phosphorylation of CHK2 by ATM, and that defects in this mechanism form the molecular basis for the RDS observed in cells deficient in mismatch repair.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Breakpoints in the ataxia telangiectasia gene arise at the RGYW somatic hypermutation motif.

The mature sporadic T-cell malignancy, T-cell prolymphocytic leukemia (T-PLL) is remarkable for frequently harbouring somatic mutations of the Ataxia Telangiectasia (A-T) gene, ATM. Because some data suggest ATM is frequently rearranged in T-PLL, it was decided to investigate such rearrangements in detail by cloning breakpoints. Among 17 T-PLL tumour samples, three rearrangements were detected by Southern blotting. Two cases harboured a unique type of intragenic duplication in which breakpoints arose at the consensus sequence RGYW/WRCY. The third case harboured a large deletion terminating within the ATM gene. Also, 13 T-cell acute lymphoblastic leukemia (T-ALL) samples were examined and one sample harboured a deletion- insertion with the RGYW motif at the breakpoint in ATM. This is the first known deleterious mutation detected in ATM in T-ALL. Interestingly, the RGYW motif is the signal for a cell-cycle regulated DNA double strand break (DSB) that initiates somatic hypermutation of immunoglobulin and, probably, T-cell receptor genes. The structures of the ATM duplications suggest they may arise from an error in somatic hypermutation. We suggest that aberrant components of somatic hypermutation may contribute to the defective DSB repair characteristic of cancer.

Adolescent↗
PubMed2005

Clinical guide for audiologic tinnitus management II: Treatment.

PURPOSE: This article is the second of 2 that address the need for basic procedures that can be used commonly by audiologists to manage patients with clinically significant tinnitus, as well as hyperacusis. The method described is termed audiologic tinnitus management (ATM). METHOD: ATM was developed specifically for use by audiologists. Although certain procedural components were adapted from the methods of tinnitus masking and tinnitus retraining therapy, ATM is uniquely and specifically defined. A detailed description of the ATM assessment procedures is provided in the companion article (J. A. Henry, T. L. Zaugg, & M. A. Schechter, 2005). The present article describes a specific clinical protocol for providing treatment with ATM. RESULTS: The treatment method described for ATM includes structured informational counseling and an individualized program of sound enhancement that can include the use of hearing aids, ear-level noise generators, combination instruments (noise generator and hearing aid combined), personal listening devices (wearable CD, tape, and MP3 players), and augmentative sound devices (e.g., tabletop sound generators). Ongoing treatment appointments involve primarily the structured counseling, evaluation, and adjustment of the use of sound devices, and assessment of treatment outcomes. The informational counseling protocol and an interview form for determining treatment outcomes are each described in step-by-step detail for direct clinical application. CONCLUSION: This article can serve as a practical clinical guide for audiologists to provide treatment for tinnitus in a uniform manner.

Habituation, Psychophysiologic↗
PubMed1998

Magnetic resonance imaging findings in 22 cases of myelitis: comparison between patients with and without multiple sclerosis.

We reviewed the magnetic resonance imaging (MRI) database of the Dent Neurologic Institute to study the abnormal findings in myelitis. We identified 22 patients, and compared non-MS-related acute transverse myelitis (ATM, n = 9), to myelitis associated with multiple sclerosis (MS-myelitis, n = 13). The ATM patients were significantly older than MS patients at the time of the myelitis diagnosis (mean age 46 vs 35, p < 0.05). ATM appeared as a "longitudinal myelitis", with fusiform cord expansion on T1-weighted images and intramedullary increased signal on T2-weighted images, each involving multiple spinal levels (mean = 7-8). However, MS-myelitis lesions appeared focal, involving significantly fewer spinal levels (mean = 1-2, p < 0.001), although the lesions were equally likely to expand the cord. Four (42%) of the ATM lesions showed abnormal, variable enhancement, whereas none of the MS myelitis lesions enhanced. Cranial MRI was more likely to be normal in ATM (78%) than in MS-myelitis patients (15%, p < 0.001). Although readily distinguishable from lesions due to MS, the various etiologies for ATM, including post-infectious (n = 2), post-vaccination (n = 3), and idiopathic (n = 4) were indistinguishable on MRI. The MRI findings of an extensively lesioned, swollen cord, suspicious for an intramedullary tumor and providing a temptation for a biopsy, may reflect a non-neoplastic inflammatory disorder.

Journal Article↗
PubMed2001

Phosphorylation of serines 635 and 645 of human Rad17 is cell cycle regulated and is required for G(1)/S checkpoint activation in response to DNA damage.

ATR [ataxia-telangiectasia-mutated (ATM)- and Rad3-related] is a protein kinase required for both DNA damage-induced cell cycle checkpoint responses and the DNA replication checkpoint that prevents mitosis before the completion of DNA synthesis. Although ATM and ATR kinases share many substrates, the different phenotypes of ATM- and ATR-deficient mice indicate that these kinases are not functionally redundant. Here we demonstrate that ATR but not ATM phosphorylates the human Rad17 (hRad17) checkpoint protein on Ser(635) and Ser(645) in vitro. In undamaged synchronized human cells, these two sites were phosphorylated in late G(1), S, and G(2)/M, but not in early-mid G(1). Treatment of cells with genotoxic stress induced phosphorylation of hRad17 in cells in early-mid G(1). Expression of kinase-inactive ATR resulted in reduced phosphorylation of these residues, but these same serine residues were phosphorylated in ionizing radiation (IR)-treated ATM-deficient human cell lines. IR-induced phosphorylation of hRad17 was also observed in ATM-deficient tissues, but induction of Ser(645) was not optimal. Expression of a hRad17 mutant, with both serine residues changed to alanine, abolished IR-induced activation of the G(1)/S checkpoint in MCF-7 cells. These results suggest ATR and hRad17 are essential components of a DNA damage response pathway in mammalian cells.

Amino Acid Sequence↗
PubMed1996

Pleiotropic defects in ataxia-telangiectasia protein-deficient mice.

We have generated a mouse model for ataxia-telangiectasia by using gene targeting to generate mice that do not express the Atm protein. Atm-deficient mice are retarded in growth, do not produce mature sperm, and exhibit severe defects in T cell maturation while going on to develop thymomas. Atm-deficient fibroblasts grow poorly in culture and display a high level of double-stranded chromosome breaks. Atm-deficient thymocytes undergo spontaneous apoptosis in vitro significantly more than controls. Atm-deficient mice then exhibit many of the same symptoms found in ataxia-telangiectasia patients and in cells derived from them. Furthermore, we demonstrate that the Atm protein exists as two discrete molecular species, and that loss of one or of both of these can lead to the development of the disease.

Animals↗
PubMed1997

The ataxia-telangiectasia gene product, a constitutively expressed nuclear protein that is not up-regulated following genome damage.

The product of the ataxia-telangiectasia gene (ATM) was identified by using an antiserum developed to a peptide corresponding to the deduced amino acid sequence. The ATM protein is a single, high-molecular weight protein predominantly confined to the nucleus of human fibroblasts, but is present in both nuclear and microsomal fractions from human lymphoblast cells and peripheral blood lymphocytes. ATM protein levels and localization remain constant throughout all stages of the cell cycle. Truncated ATM protein was not detected in lymphoblasts from ataxia-telangiectasia patients homozygous for mutations leading to premature protein termination. Exposure of normal human cells to gamma-irradiation and the radiomimetic drug neocarzinostatin had no effect on ATM protein levels, in contrast to a noted rise in p53 levels over the same time interval. These findings are consistent with a role for the ATM protein in ensuring the fidelity of DNA repair and cell cycle regulation following genome damage.

Antibodies↗
PubMed2001

Residual ataxia telangiectasia mutated protein function in cells from ataxia telangiectasia patients, with 5762ins137 and 7271T-->G mutations, showing a less severe phenotype.

We have assessed several ataxia Telangiectasia mutated (ATM)-dependent functions in cells derived from ataxia telangiectasia patients, carrying either an ATM 5762ins137 splice site or a 7271T-->G missense mutation, with a less severe phenotype compared with the classical disorder. ATM kinase in vitro, from 5762ins137 cells, showed the same specific activity as ATM in normal cells, but the protein was present at low levels. In contrast, mutant ATM kinase activity in the 7271T-->G cells was only about 6% that of the activity in normal cells, although the level of mutant protein expressed was similar to normal cells. Phosphorylation of the DNA double strand break repair proteins Nbs1 and hMre11, following DNA damage, was observed in normal and 7271T-->G cells but was almost absent in both 5762ins137 and classical ataxia telangiectasia cells. The kinetics of p53 response was intermediate between normal and classical ataxia telangiectasia cells in both the 7271T-->G and 5762ins137 cells, but interestingly, c-Jun kinase activation following DNA damage was equally deficient in cell lines derived from all the ataxia telangiectasia patients. Our results indicate that levels of ATM kinase activity, but not induction of p53 or c-Jun kinase activity, in these cells correlate with the degree of neurological disorder in the patients.

Ataxia Telangiectasia↗
PubMed2007

Coregulated ataxia telangiectasia-mutated and casein kinase sites modulate cAMP-response element-binding protein-coactivator interactions in response to DNA damage.

The cyclic AMP-response element-binding protein (CREB) is a bZIP family transcription factor implicated as an oncoprotein and neuron survival factor. CREB is activated in response to cellular stimuli, including cAMP and Ca(2+), via phosphorylation of Ser-133, which promotes interaction between the kinase-inducible domain (KID) of CREB and the KID-interacting domain of CREB-binding protein (CBP). We previously demonstrated that the interaction between CREB and CBP is inhibited by DNA-damaging stimuli through a mechanism whereby CREB is phosphorylated by the ataxia telangiectasia-mutated (ATM) protein kinase. We now show that the ATM phosphorylation sites in CREB are functionally intertwined with a cluster of coregulated casein kinase (CK) sites. We demonstrate that DNA damage-induced phosphorylation of CREB occurs in three steps. The initial event in the CREB phosphorylation cascade is the phosphorylation of Ser-111, which is carried out by CK1 and CK2 under basal conditions and by ATM in response to ionizing radiation. The phosphorylation of Ser-111 triggers the CK2-dependent phosphorylation of Ser-108 and the CK1-dependent phosphorylation of Ser-114 and Ser-117. The phosphorylation of Ser-114 and Ser-117 by CK1 then renders CREB permissive for ATM-dependent phosphorylation on Ser-121. Mutation of Ser-121 alone abrogates ionizing radiation-dependent repression of CREB-CBP complexes, which can be recapitulated using a CK1 inhibitor. Our findings outline a complex mechanism of CREB phosphorylation in which coregulated ATM and CK sites control CREB transactivation potential by modulating its CBP-binding affinity. The coregulated ATM and CK sites identified in CREB may constitute a signaling motif that is common to other DNA damage-regulated substrates.

Animals↗
PubMed1995

Molecular dynamics simulation of anesthetic-phospholipid bilayer interactions.

To probe the hypothesis of a lipid-mediated mechanism of general anesthetic action on a molecular level, and to help elucidate the nature of the interactions of bioactive compounds with membranes, the effects of trichloroethylene (TCE), an inhalational general anesthetic, on a dioleoylphosphatidylcholine (DOPC) lipid bilayer have been investigated by molecular dynamics (MD) simulations at 37 degrees C and 1 atm and the results compared with 31P and 2H NMR experimental studies (Ref 1). The model used included a single TCE molecule embedded in a lipid bilayer consisting of 24 DOPC molecules and an 8 A layer of explicit water of solvation in each polar head group region of the bilayer, together with constant-pressure periodic boundary conditions in three dimensions. A comparison of the bilayer properties calculated in the presence and absence of the anesthetic led to the detection of three major perturbations of the bilayer caused by the anesthetic at 1 atm: i) an increase in the ratio of the effective areas of hydrocarbon tails and the head group per lipid, predicting the tendency of lipids near the anesthetic site of action to form a hexagonal phase (HII); ii) a slight increase in the frequency of chain dihedral angles found in the gauche conformation; and iii) a significant increase in the lateral mean-square displacement of lipid molecules, an indication of increased lipid lateral diffusion and membrane fluidity. The pressure antagonism of these effects was also studied by MD simulations at pressures of 200 and 400 atm. The study of the pressure reversibility of these effects at 200 and 400 atm indicated that they were partially prevented at 200 atm and essentially blocked at 400 atm, suggesting their probable relevance to the pressure reversal effect seen with general anesthesia. These results may thus provide insights into the interaction between general anesthetics and similar small organic molecules with membranes.

Computer Graphics↗
PubMed2006

Regulation of ATM/p53-dependent suppression of myc-induced lymphomas by Wip1 phosphatase.

The ataxia telangiectasia mutated (ATM) kinase is a key tumor suppressor that regulates numerous cell cycle checkpoints as well as apoptosis. Here, we report that ATM is a critical player in the regulation of apoptosis and lymphomagenesis in the presence of c-myc. In turn, deletion of the inhibitory ATM phosphatase, Wip1, results in ATM up-regulation and suppression of Emicro-myc-induced B cell lymphomas. Using mouse genetic crosses, we show that the onset of myc-induced lymphomas is dramatically delayed in Wip1-null mice in an ATM- and p53-, but not p38 MAPK- or Arf-, dependent manner. We propose that Wip1 phosphatase is critical for regulating the ATM-mediated tumor surveillance network.

Animals↗