PubMed Health⌕ Search

Biomedical subjects

Stephen Lee

Publications and source records attributed to Stephen Lee.

At least 19 recordsLinked to original sources
PubMed2007

Pd(0.213)Cd(0.787) and Pd(0.235)Cd(0.765) structures: their long c axis and composite crystals, chemical twinning, and atomic site preferences.

We present single-crystal studies of Pd(0.213)Cd(0.787) and Pd(0.235)Cd(0.765), synchrotron powder studies of Pd(1-x)Cd(x), 0.755> or =x> or =0.800, and LDA-DFT and extended Hückel (eH) calculations on these or related phases. The two single-crystal structures have a, b, and c axis lengths of 9.9013(7), 14.0033(10), 37.063(24) and 9.9251(3), 14.0212(7), 60.181(3) A, respectively and they crystallize in the space groups Ccme and F2mm, respectively (solved as (3+1)-dimensional crystals their most convenient superspace group is Xmmm(00gamma)s00). The structures have two different structural components each with their own separate axis parameters. Powder data shows that the ratio of these separate axes (S/L) varies from 1.615 to 1.64, values near the golden mean (1.618). For Pd(0.213)Cd(0.787), different Pd and Cd site occupancies lead to variation in the R factor from 2.6-3.6 %. The site occupancy pattern with the lowest R factor (among the 26 820 variants studied) is the exact site occupancy pattern predicted by LDA-DFT parameterized eH Mulliken charge populations. The phases can be understood through a chemical twinning principle found in gamma-brass, the parent structure for the above phases (a relation with the MgCu(2) Laves phase is also noted). This twinning principle can be used to account for Cd and Pd site preferences. At the same time there is a clean separation among the Cd and Pd atoms for the two separate chain types at height b=0 and 1/2. These results indicate that Cd:Pd stoichiometry plays a role in phase stability.

Cadmium↗
PubMed2006

Restriction of rRNA synthesis by VHL maintains energy equilibrium under hypoxia.

Biological evolution abides by an unbending rule obligating organisms to maintain energy equilibrium. Hypoxia reduces cellular energy supply and is thus thought to be deleterious. We report that cells have evolved pH-sensitive mechanisms to maintain energy equilibrium by lowering energy demand. We found that fermentation-induced acidosis allows hypoxic cells to maintain energy equilibrium and viability under hypoxia by restricting ribosomal biogenesis, the most energy-demanding cellular process. Acidosis triggers nucleolar condensation, decreases precursor rRNA synthesis, reduces the dynamic profile of the RNA polymerase I preinitiation factor UBF1 and its interaction with the promoter of rRNA genes (rDNA). These changes require the pH-dependent interaction of the statically detained von Hippel-Lindau tumor suppressor protein (VHL) with rDNA. This phenomenon is promoted by, but does not require, activation of the hypoxia-inducible factor (HIF), a transcription factor implicated in extracellular acidification, energy production and oxygen homeostasis. Abrogating this program by silencing VHL expression, competing rDNA-VHL interaction or preventing environmental acidification triggers energy starvation and cell death under hypoxia. Our data suggest that oxygen-starved cells maintain energy equilibrium by gauging the environmental concentration of H(+) to statically detain VHL to nucleolar rDNA and restrict ribosome production. These findings also provide an explanation for the protective effect of acidosis in ischemic settings such as development, stroke and cancer.

3T3 Cells↗
PubMed2006

Two-dimensional double metal cyanide complexes: highly active catalysts for the homopolymerization of propylene oxide and copolymerization of propylene oxide and carbon dioxide.

The synthesis of two-dimensional double metal cyanide complexes of the formula Co(H2O)2[M(CN)4].4H2O (M=Ni, Pd or Pt) and the X-ray crystal structure of Co(H2O)2[Pd(CN)4].4H2O are presented. The anhydrous forms of these complexes were found to be effective catalyst precursors for the homopolymerization of propylene oxide as well as the random copolymerization of propylene oxide and carbon dioxide to produce poly(propylene oxide-co-propylene carbonate) with no propylene carbonate byproduct. A detailed copolymer microstructure is proposed.

Journal Article↗
PubMed2006

Multiple acquired renal carcinoma tumor capabilities abolished upon silencing of ADAM17.

Malignancy is a manifestation of acquired defects in regulatory circuits that direct normal cell proliferation and homeostasis. Most of these circuits operate through cell autonomous pathways, whereas others potentially involve the neighboring microenvironment. We report that the metalloprotease ADAM17 plays a pivotal role in several acquired tumor cell capabilities by mediating the availability of soluble transforming growth factor-alpha, an epidermal growth factor receptor (EGFR) ligand, and thus the establishment of a key autocrine signaling pathway. Silencing of ADAM17 in human renal carcinoma cell lines corrects critical features associated with cancer cells, including growth autonomy, tumor inflammation, and tissue invasion. Highly malignant renal carcinoma cancer cells fail to form in vivo tumors in the absence of ADAM17, confirming the essential function of this molecule in tumorigenesis. These data show that ligand shedding is a crucial step in endogenous EGFR activation and endorse prospective therapeutic strategies targeting ADAM17 in human cancer.

ADAM Proteins↗
PubMed2006

Impairment of microtubule-dependent trafficking by overexpression of alpha-synuclein.

Abnormal accumulation of alpha-synuclein (alpha-syn) has been linked to several neurological disorders, including Parkinson's disease (PD). However, the underlying mechanism by which alpha-syn accumulation affects neuronal function and survival remains unknown. Here, we provide data suggesting a possible effect of aggregated alpha-syn on the microtubule (MT) network. Consistent with the MT dysfunction, we also observed other degenerative changes, such as neuritic degeneration, trafficking defects, and Golgi fragmentation, which are common pathological features shared by many human neurodegenerative diseases. Neuritic degeneration and Golgi fragmentation were confirmed in primary cultures of dorsal root ganglia (DRG) neurons overexpressing alpha-syn. This effect of alpha-syn seems to have some selectivity to the MT system, as actin microfilaments and MT-independent trafficking remain unaffected. Within the degenerating neurites, we found numerous spherical co-aggregates of alpha-syn and tubulins, from which actin was excluded. These studies suggest that the MT system is a potential target of alpha-syn, and impairment of this system might have impacts on neuronal structure and function.

Actin Cytoskeleton↗
PubMed2005

The maximin principle of pi-radical packings.

A two-term model is proposed for hydrocarbon and N-containing pi-radicals which are in close contact with one another. The first term is attractive (due to partially occupied frontier pi-orbitals), and the second, repulsive (due to hard-core repulsion between close-lying atoms). This model is applied to dimers where intermolecular contacts are closer than <0.95 x the sum of the atomic van der Waals radii. The maximin principle is proposed. The maximin principle states that the lowest energy conformation maximizes overlap of the frontier orbitals while simultaneously minimizing intermolecular contacts. A Hückel Hamiltonian, the mu(2)-Hamiltonian, which contains the above attractive and repulsive terms, is applied. The interaction surfaces of two pi-hydrocarbon radical cations were calculated for the three systems known crystallographically to contain cations in close contact: naphthalene, fluoranthene, and pyrene. The global minima of these surfaces correspond to the experimentally determined structures. The mu(2)-Hamiltonian energy surfaces of the naphthalene cation dimer are qualitatively similar to those calculated at the RHF/6-311G(d,p) and MP2/6-311G(d,p) levels. The maximin principle is applied to N-containing pi-radicals. Except in the case of tetracyanoethene, the maximin principle correctly predicts the most common dimer crystal packing. (MgPc)(NO(3)).0.5THF and (MgPc)(ReO(4)).1.5THF (Pc = phthalocyanine) were prepared: both new crystal structures follow the maximin principle. The maximin principle is used to suggest the dimer cation ground state of oligoacenes, cations important as organic hole-based semiconductors.

Cations↗
PubMed2005

Regulation of ubiquitin ligase dynamics by the nucleolus.

Cellular pathways relay information through dynamic protein interactions. We have assessed the kinetic properties of the murine double minute protein (MDM2) and von Hippel-Lindau (VHL) ubiquitin ligases in living cells under physiological conditions that alter the stability of their respective p53 and hypoxia-inducible factor substrates. Photobleaching experiments reveal that MDM2 and VHL are highly mobile proteins in settings where their substrates are efficiently degraded. The nucleolar architecture converts MDM2 and VHL to a static state in response to regulatory cues that are associated with substrate stability. After signal termination, the nucleolus is able to rapidly release these proteins from static detention, thereby restoring their high mobility profiles. A protein surface region of VHL's beta-sheet domain was identified as a discrete [H+]-responsive nucleolar detention signal that targets the VHL/Cullin-2 ubiquitin ligase complex to nucleoli in response to physiological fluctuations in environmental pH. Data shown here provide the first evidence that cells have evolved a mechanism to regulate molecular networks by reversibly switching proteins between a mobile and static state.

Amino Acid Sequence↗
PubMed2005

Silencing of epidermal growth factor receptor suppresses hypoxia-inducible factor-2-driven VHL-/- renal cancer.

Inactivating mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are associated with clear cell renal cell carcinoma (VHL-/- RCC), the most frequent malignancy of the human kidney. The VHL protein targets the alpha subunits of hypoxia-inducible factor (HIF) transcription factor for ubiquitination and degradation. VHL-/- RCC cells fail to degrade HIF resulting in the constitutive activation of its target genes, a process that is required for tumorigenesis. We recently reported that HIF activates the transforming growth factor-alpha/epidermal growth factor receptor (TGF-alpha/EGFR) pathway in VHL-defective RCC cells. Here, we show that short hairpin RNA (shRNA)-mediated inhibition of EGFR is sufficient to abolish HIF-dependent tumorigenesis in multiple VHL-/- RCC cell lines. The 2alpha form of HIF (HIF-2alpha), but not HIF-1alpha, drives in vitro and in vivo tumorigenesis of VHL-/- RCC cells by specifically activating the TGF-alpha/EGFR pathway. Transient incubation of VHL-/- RCC cell lines with small interfering RNA directed against EGFR prevents autonomous growth in two-dimensional culture as well as the ability of these cells to form dense spheroids in a three-dimensional in vitro tumor assay. Stable expression of shRNA against EGFR does not alter characteristics associated with VHL loss including constitutive production of HIF targets and defects in fibronectin deposition. In spite of this, silencing of EGFR efficiently abolishes in vivo tumor growth of VHL loss RCC cells. These data identify EGFR as a critical determinant of HIF-2alpha-dependent tumorigenesis and show at the molecular level that EGFR remains a credible target for therapeutic strategies against VHL-/- renal carcinoma.

Basic Helix-Loop-Helix Proteins↗
PubMed2005

Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia.

DNA methylation is associated with malignant transformation, but limitations imposed by genetic variability, tumor heterogeneity, availability of paired normal tissues and methodologies for global assessment of DNA methylation have limited progress in understanding the extent of epigenetic events in the initiation and progression of human cancer and in identifying genes that undergo methylation during cancer. We developed a mouse model of T/natural killer acute lymphoblastic leukemia that is always preceded by polyclonal lymphocyte expansion to determine how aberrant promoter DNA methylation and consequent gene silencing might be contributing to leukemic transformation. We used restriction landmark genomic scanning with this mouse model of preleukemia reproducibly progressing to leukemia to show that specific genomic methylation is associated with only the leukemic phase and is not random. We also identified Idb4 as a putative tumor-suppressor gene that is methylated in most mouse and human leukemias but in only a minority of other human cancers.

Animals↗
PubMed2005

Imaging of acute appendicitis: US as the primary imaging modality.

BACKGROUND: The investigation of the acute abdomen in infants and children has evolved during the last two decades, placing imagers at the forefront of the evaluation and diagnosis of acute right lower quadrant abdominal problems. US and CT have recently been shown to be equally accurate in the diagnosis of acute appendicitis, but not everyone agrees. OBJECTIVE: To demonstrate the efficacy of triaging patients with acute abdominal problems that suggest appendicitis with US as the primary imaging modality. MATERIALS AND METHODS: We retrospectively reviewed the prospective imaging diagnoses in 622 children who presented to our emergency room (ER) and clinics with acute abdominal symptoms suggestive of appendicitis. We documented whether US or CT was performed and noted the diagnoses made. All of the patients had plain films. In addition, all patients undergoing surgical appendectomy during this time were also documented so as not to miss any cases of appendicitis. None was missed. RESULTS: There were 622 consecutive patients in our study. Three patients, diagnosed as normal, were eventually excluded because of lack of follow-up. In all, 152 patients were evaluated clinically and with plain films only. They were not subject to surgical exploration or further imaging. None returned with appendicitis. Eighty-one patients were directly subject to laparotomy after clinical and plain film evaluation. Of these patients, 20% had a normal appendix. Of the remaining 389 patients, 386 had US and three had CT alone. Four patients had both CT and US because of an inconclusive US examination. Three patients had CT alone because of their size. In total, 137 patients were diagnosed with appendicitis with US and/or CT. Four of these patients (3%) had normal appendices. Forty-two patients (less three lost to follow-up) were diagnosed as normal, and none returned with findings of appendicitis. Nine others had conditions other than acute appendicitis. Three had surgically proven, nonrelated conditions, and of the other six, one had pancreatitis and five nonsurgical adnexal problems. In all, 201 patients were diagnosed (with US) with mesenteric adenitis-enteritis, and none returned with findings of appendicitis. CONCLUSION: We attained a high degree of diagnostic accuracy in patients presenting with findings suggestive of appendicitis using US as the primary imaging modality. Our false-positive appendectomy rate was 3%. Therefore, triage of the acute abdomen with US supported by CT when required has considerable merit, especially when considering that US is noninvasive and does not use ionizing radiation.

Abdomen, Acute↗
PubMed2005

Small amphiphilic organics, coordination extended solids, and constant curvature structures.

In this Account, we explore the role constant curvature structures play in amphiphilic small molecule crystals and extended coordination solids. A constant curvature structure is one in which there is a surface or interface that has the same curvature throughout its surface. Simple examples of such structures contain spheres (micelles), columns, or layers. Yet another family are cubic as is found in the gyroid topology. For amphiphilic systems, there are two domains, one generally hydrophobic and the other hydrophilic. We find that the interfaces between these two domains in small molecule structures resemble those in larger scale systems and adopt topologies related to constant curvature structures. The hydrophobic-to-total volume ratio, a molecular parameter, can be used to predict which type of constant curvature structure is adopted. In the case of three coordinate extended solids, constant curvature plays a role both in the extended net topology and in the hydrophobic-to-hydrophilic interface.

Journal Article↗
PubMed2005

Dysplastic naevi: to shave, or not to shave? A retrospective study of the use of the shave biopsy technique in the initial management of dysplastic naevi.

The management of dysplastic naevi is a controversial subject. This study sought to assess the usefulness of the shave biopsy technique in the initial management of dysplastic naevi, and to demonstrate the advantages over the punch biopsy technique. We report a retrospective observational study of histopathology specimens examined in one histopathology practice over a 14-month period. Patients who had a clinical diagnosis of 'dysplastic naevus', which had initially been biopsied using either a shave or punch biopsy, and then followed up with a full-thickness elliptical excision, were included in the study. Histopathological concordance between the shave and punch biopsy specimens and their respective follow-up elliptical excisions was compared. We found that 21 of 22 (95.5%) shave biopsies were concordant with their respective excision specimens, and that 29 of 41 (70.7%) punch biopsies were concordant with their respective elliptical excision specimens. Of the shave biopsy specimens reviewed, 66% showed that the dysplastic naevi were completely excised with the initial biopsy, compared with 21.2% of the punch biopsy specimens. These findings confirm that shave biopsies provide accurate diagnostic information in the assessment of dysplastic naevi. Shave biopsies enable the entire lesion to be submitted for histopathological assessment, improving the chances of an accurate diagnosis.

Adult↗
PubMed2005

Polymorphisms of microsomal epoxide hydrolase in French vinyl chloride workers.

OBJECTIVES: The purpose of this study was to determine if polymorphisms in microsomal epoxide hydrolase, an enzyme involved in the metabolism of reactive intermediates of vinyl chloride (VC), contribute to the variable susceptibility to the mutagenic effects of vinyl chloride among exposed workers. MATERIALS AND METHODS: Polymorphisms at codons 113 and 139 were determined in DNA samples from 211 French vinyl chloride workers. Genotypes were stratified into low, medium and high activity groups and odds ratios and 95% confidence intervals were determined for the presence of one or both of two VC-induced mutant biomarkers (mutant ras-p21 and mutant p53) by logistic regression adjusting for age, smoking, drinking and cumulative VC exposure. RESULTS: Compared to the low-activity microsomal epoxide hydrolase genotype stratum, the odds ratio for the presence of the VC-induced mutant biomarkers increased to 1.16 (95% CI: 0.64-2.10) in the medium-activity genotype stratum and to 1.35 (95% CI: 0.66-2.77) in the high-activity genotype stratum. The test for trend was not statistically significant and was in the opposite direction from that expected based on increasing removal of reactive intermediates with increasing activity. CONCLUSIONS: The results suggest that polymorphisms in microsomal epoxide hydrolase do not play a significant role in susceptibility to the mutagenic effects of vinyl chloride.

Adult↗
PubMed2004

The Nowotny chimney ladder phases: following the c(pseudo) clue toward an explanation of the 14 electron rule.

We account for two empirical rules of the Nowotny chimney ladder phases (NCLs, intermetallic compounds of the form T(t)E(m); T, groups 4-9; E, groups 13-15). The first rule is that for late transition metal NCLs the total number of valence electrons per T atom is 14. The second is the appearance of a pseudoperiodicity with a spacing, c(pseudo), which is directly related to the stoichiometry, T(t)E(m), by (2t - m) c(pseudo)= c. Both rules are accounted for by viewing the NCLs as twinned structures constructed from blocks of the parent compound, RuGa(2) of thickness c(pseudo)/2, with the successive layers rotated relative to each other by 90 degrees. Sterically encumbered E atoms are then deleted at the interfaces between layers, followed by relaxation.

Journal Article↗
PubMed2004

The Nowotny chimney ladder phases: whence the 14 electron rule?

The late transition metal Nowotny chimney ladder phases (NCLs, T(t)E(m); T, groups 7-9; E, groups 13 and 14) follow a 14 electron rule: the total number of valence electrons per T atom is 14. In this paper, we extract a chemical explanation for this rule from extended Hückel calculations; we focus on RuGa(2), the parent NCL structure. A gap between filled and unfilled bands arises from the occupation of two Ga-Ga bonding/Ru-Ga nonbonding orbitals per RuGa(2), independent of k-point. In addition, the five Ru d levels are filled. Together this makes for 7 filled bands at each k-point, or 14 electrons per Ru. We discuss the connections between this 14 electron rule and the 18 electron rule of organometallic complexes.

Journal Article↗
PubMed2004

Structure-composition relations for the partly disordered Hume-Rothery phase Ir7+7deltaZn97-11delta (0.31< or =delta< or =0.58).

The crystal structure, its variation within the homogeneity range and some physical properties of the new zinc-rich, partly disordered phase Ir7+7deltaZn97-11delta (0.31< or =delta< or =0.58) are reported. The structures of three phases with distinct composition were determined by means of single crystal X-ray diffraction. Ir7+7deltaZn97-11delta exhibits a significant homogeneity range, adopts a complex gamma-brass related cubic structure (cF403-406), is stable up to 1201(2) K, and transforms sluggishly below 1048(4) K into a phase with 394 atoms in the monoclinic primitive unit cell. It is a diamagnetic, moderate metallic conductor. Six distinguishable clusters consisting of 22-29 atoms comprise the structure. The clusters are situated about the 16 high symmetry points of the cubic F lattice. The structure can be subdivided into two partial structures, one with constant composition IrZn5 and 192 atoms per unit cell and a second being significantly richer in zinc with variable composition and 211-214 atoms per unit cell. The meandering triply periodic minimal surface of two interpenetrating diamond-like nets separates the compositionally variable from its complementary invariant part. The phase width is coupled with substitutional and positional disorder. A comprehensive analysis of composition-dependent site occupancy factors reveals a linear correlation between the various types of disorder which can be conclusively interpreted in terms of an incoherent intergrowth of distinctive partial structures in variable proportions on a length scale comparable to the size of the approximately 2 nm large unit cell. On the basis of the structural findings we derive the structure chemically meaningful formula Ir7+7delta)Zn97-11delta which quantitatively accounts for the interrelation between substitutional and positional disorder and provides a measure for the homogeneity range in structural terms.

Alloys↗
PubMed2004

Oxygen sensing by H+: implications for HIF and hypoxic cell memory.

Hypoxia and acidosis are common features of several physiological and pathological situations, including cancer and stroke. The HIF (hypoxia-inducible factor) transcription factor plays a seminal role in orchestrating cellular responses to alterations in oxygen availability. HIF is degraded in normal oxygen tension by the VHL (von Hippel-Lindau) tumor suppressor protein but stabilized by hypoxia to activate an array of genes implicated in oxygen homeostasis including vascular endothelial growth factor. Cells respond to a comparatively mild decline in oxygen tension by converting to an anaerobic state of respiration and secreting lactic acid. We recently reported that a decrease in environmental pH triggers sequestration of VHL into the nucleolus neutralizing its ability to degrade HIF. This implies that cells have evolved a parallel mechanism of HIF activation that responds to changes in oxygen levels by sensing extracellular [H+]. Here we discuss the implications of this new VHL regulatory mechanism on oxygen homeostasis and hypoxic cell memory.

Aryl Hydrocarbon Receptor Nuclear Translocator↗