Length-dependent thermopower of highly conducting Au-C bonded single molecule junctions.

We report the simultaneous measurement of conductance and thermopower of highly conducting single-molecule junctions using a scanning tunneling microscope-based break-junction setup. We start with molecular backbones (alkanes and oligophenyls) terminated with trimethyltin end groups that cleave off in situ to create junctions where terminal carbons are covalently bonded to the Au electrodes. We apply a thermal gradient across these junctions and measure their conductance and thermopower. Because of the electronic properties of the highly conducting Au-C links, the thermoelectric properties and power factor are very high. Our results show that the molecular thermopower increases nonlinearly with the molecular length while conductance decreases exponentially with increasing molecular length. Density functional theory calculations show that a gateway state representing the Au-C covalent bond plays a key role in the conductance. With this as input, we analyze a series of simplified models and show that a tight-binding model that explicitly includes the gateway states and the molecular backbone states accurately captures the experimentally measured conductance and thermopower trends.

Probing the conductance superposition law in single-molecule circuits with parallel paths.

According to Kirchhoff's circuit laws, the net conductance of two parallel components in an electronic circuit is the sum of the individual conductances. However, when the circuit dimensions are comparable to the electronic phase coherence length, quantum interference effects play a critical role, as exemplified by the Aharonov-Bohm effect in metal rings. At the molecular scale, interference effects dramatically reduce the electron transfer rate through a meta-connected benzene ring when compared with a para-connected benzene ring. For longer conjugated and cross-conjugated molecules, destructive interference effects have been observed in the tunnelling conductance through molecular junctions. Here, we investigate the conductance superposition law for parallel components in single-molecule circuits, particularly the role of interference. We synthesize a series of molecular systems that contain either one backbone or two backbones in parallel, bonded together cofacially by a common linker on each end. Single-molecule conductance measurements and transport calculations based on density functional theory show that the conductance of a double-backbone molecular junction can be more than twice that of a single-backbone junction, providing clear evidence for constructive interference.

In situ formation of highly conducting covalent Au-C contacts for single-molecule junctions.

Charge transport across metal-molecule interfaces has an important role in organic electronics. Typically, chemical link groups such as thiols or amines are used to bind organic molecules to metal electrodes in single-molecule circuits, with these groups controlling both the physical structure and the electronic coupling at the interface. Direct metal-carbon coupling has been shown through C60, benzene and π-stacked benzene, but ideally the carbon backbone of the molecule should be covalently bonded to the electrode without intervening link groups. Here, we demonstrate a method to create junctions with such contacts. Trimethyl tin (SnMe(3))-terminated polymethylene chains are used to form single-molecule junctions with a break-junction technique. Gold atoms at the electrode displace the SnMe(3) linkers, leading to the formation of direct Au-C bonded single-molecule junctions with a conductance that is ∼100 times larger than analogous alkanes with most other terminations. The conductance of these Au-C bonded alkanes decreases exponentially with molecular length, with a decay constant of 0.97 per methylene, consistent with a non-resonant transport mechanism. Control experiments and ab initio calculations show that high conductances are achieved because a covalent Au-C sigma (σ) bond is formed. This offers a new method for making reproducible and highly conducting metal-organic contacts.

Plasmonic control of the shape of the Raman spectrum of a single molecule in a silver nanoparticle dimer.

We study surface-enhanced Raman scattering (SERS) of individual organic molecules embedded in dimers of two metal nanoparticles. The good control of the dimer preparation process, based on the usage of bifunctional molecules, enables us to study quantitatively the effect of the nanoparticle size on the SERS intensity and spectrum at the single molecule level. We find that as the nanoparticle size increases the total Raman intensity increases and the lower energy Raman modes become dominant. We perform an electromagnetic calculation of the Raman enhancement and show that this behavior can be understood in terms of the overlap between the plasmonic modes of the dimer structure and the Raman spectrum. As the nanoparticle size increases, the plasmonic dipolar mode shifts to longer wavelength and thereby its overlap with the Raman spectrum changes. This suggests that the dimer structure can provide an external control of the emission properties of a single molecule. Indeed, clear and systematic differences are observed between Raman spectra of individual molecules adsorbed on small versus large particles.

Cyclodextrin dimers as cleavable carriers of photodynamic sensitizers.

Several phthalocyanines carrying hydrophobic components have been synthesized and shown to bind to a group of cyclodextrin dimers with a carbon-carbon double bond in the linker. The complexes are soluble in water. On irradiation in the presence of oxygen, the singlet oxygen produced cleaves the olefinic linkers in the complexes, resulting in precipitation of the sensitizers. This process concentrates the sensitizers in the light beam, a process that has useful potential in photodynamic therapy.

Histone deacetylase inhibitors as new cancer drugs.

Histone deacetylase inhibitors are potent inducers of growth arrest, differentiation, or apoptotic cell death in a variety of transformed cells in culture and in tumor bearing animals. Histone deacetylases and the family of histone acetyl transferases are involved in determining the acetylation of histones, which play a role in regulation of gene expression. Radiograph crystallographic studies reveal that the histone deacetylase inhibitors, suberoylanilide hydroxamic acid and trichostatin A, fit into the catalytic site of histone deacetylase, which has a tubular structure with a zinc atom at its base. The hydroxamic acid moiety of the inhibitor binds to the zinc. Histone deacetylase inhibitors cause acetylated histones to accumulate in both tumor and peripheral circulating mononuclear cells. Accumulation of acetylated histones has been used as a marker of the biologic activity of the agents. Hydroxamic acid-based histone deacetylase inhibitors limit tumor cell growth in animals with little or no toxicity. These compounds act selectively on genes, altering the transcription of only approximately 2% of expressed genes in cultured tumor cells. A number of proteins other than histones are substrates for histone deacetylases. The role that these other targets play in histone deacetylase inducement of cell growth arrest, differentiation, or apoptotic cell death is not known. This review summarizes the characteristics of a variety of inhibitors of histone deacetylases and their effects on transformed cells in culture and tumor growth in animal models. Several structurally different histone deacetylase inhibitors are in phase I or II clinical trials in patients with cancers.

Long-term recreational physical activity and breast cancer in the National Health and Nutrition Examination Survey I epidemiologic follow-up study.

Our purpose was to study the association between long-term recreational physical activity and breast cancer in the Epidemiological Follow-up Study (NHEFS) of the first National Health and Nutrition Examination Survey (NHANES I, 1971-1975). The analytic cohort included 6160 women who were free of breast cancer at the first NHEFS follow-up in 1982-1984 and had interview data on recreational physical activity (low, moderate, and high) in 1982-1984 and 10 years earlier, in 1971-1975. We created categories of long-term (1982-1984 + 1971-1975) recreational physical activity: (a) consistently low; (b) moderate/inconsistent; and (c) consistently high. Data were analyzed using Cox proportional hazard regression models. A total of 138 women developed breast cancer between 1982-1984 and 1992. In women > or =50 years of age in 1982-1984, consistently high (versus consistently low) recreational physical activity was associated with a 67% reduction in breast cancer risk (n = 96 cases; relative risk, 0.33; 95% confidence interval, 0.14-0.82; P for trend = 0.03); in women <50 years of age (n = 42 cases), there was no association. Associations were not modified by body mass index or by weight gain as an adult. High recreational physical activity over the long-term may reduce breast cancer risk in women > or =50 years of age; in this sample, it did so regardless of weight history.

Inhibition of transformed cell growth and induction of cellular differentiation by pyroxamide, an inhibitor of histone deacetylase.

PURPOSE: We have synthesized a series of hybrid polar compounds that induce differentiation and/or apoptosis of various transformed cells. These agents are also potent inhibitors of histone deacetylases (HDACs). Pyroxamide (suberoyl-3-aminopyridineamide hydroxamic acid) is a new member of this class of compounds that is currently under development as an anticancer agent. We investigated the activity of pyroxamide as an inducer of differentiation and/or apoptosis in transformed cells. EXPERIMENTAL DESIGN AND RESULTS: Pyroxamide, at micromolar concentrations, induced terminal differentiation in murine erythroleukemia (MEL) cells and caused growth inhibition by cell cycle arrest and/or apoptosis in MEL, prostate carcinoma, bladder carcinoma, and neuroblastoma cells. Administration of pyroxamide (100 or 200 mg/kg/day) to nude mice at doses that caused little evident toxicity significantly suppressed the growth of s.c. CWR22 prostate cancer xenografts. Despite the potent growth-inhibitory effects of pyroxamide in this tumor model, serum prostate-specific antigen levels in control versus pyroxamide-treated mice were not significantly different. Pyroxamide is a potent inhibitor of affinity-purified HDAC1 (ID(50) = 100 nM) and causes the accumulation of acetylated core histones in MEL cells cultured with the agent. Human CWR22 prostate tumor xenografts from mice treated with pyroxamide (100 or 200 mg/kg/day) showed increased levels of histone acetylation and increased expression of the cell cycle regulator p21/WAF1, compared with tumors from vehicle-treated control animals. CONCLUSIONS: The findings suggest that pyroxamide may be a useful agent for the treatment of malignancy and that induction of p21/WAF1 in transformed cells by pyroxamide may contribute to the antitumor effects of this agent.

Regioselective oxidation of steroids by a manganese porphyrin carrying metal coordinating groups.

A manganese porphyrin having four 2,2'-bipyridyl groups on its meso positions was synthesized. In the presence of Cu2+ ions it catalyzes the regioselective oxidation of steroid substrates carrying auxiliary metal coordinating groups.

Histone deacetylases and cancer: causes and therapies.

Together, histone acetyltransferases and histone deacetylases (HDACs) determine the acetylation status of histones. This acetylation affects the regulation of gene expression, and inhibitors of HDACs have been found to cause growth arrest, differentiation and/or apoptosis of many tumours cells by altering the transcription of a small number of genes. HDAC inhibitors are proving to be an exciting therapeutic approach to cancer, but how do they exert this effect?

Concerning two-metal cooperativity in model phosphate hydrolysis.

Three series of bimetallic ligands were tested for cooperativity in the hydrolysis of phosphate esters. It was shown that rate enhancements were in part contributed by binding to the hydrophobic linkers when the substrates were also hydrophobic, and two metal cooperativity was not found to be present. Kinetic order tests were performed and shown to be superior to previous methods for analyzing cooperativity.

Biomimetic selectivity.

Synthetic organic chemistry normally achieves selectivity by manipulation of the intrinsic reactivity of the substrate, but enzyme use is quite a different principle. The geometry of the enzyme-substrate complex determines enzymatic selectivity, completely overwhelming any normal selective reactivities. Biomimetic chemistry aims to imitate the enzymatic style. Some early approaches used attached reagents or templates to direct photochemical and free radical processes, with a combination of geometric and reactivity control. Recent work uses a mimic of the enzyme class cytochrome P-450 to achieve the selective hydroxylations of steroids with complete domination by the geometry of the catalyst-substrate complex.

Protection from sun exposure in US white children ages 6 months to 11 years.

OBJECTIVES: To estimate the prevalence of protection from sun exposure among US white children ages 6 months to 11 years. METHODS: During the summer of 1998, using telephone directory lists supplemented by random-digit dialing, the authors surveyed parents living in the contiguous United States. They calculated weighted prevalence estimates for protection methods and conducted logistic regression analyses to determine parent and child characteristics predictive of protection behaviors. RESULTS: Parents of 1,055 white children were interviewed. Children spent a median of 20 hours per week outdoors during the summer, of which 10 hours were at school. Sunscreen (61.8%, 95% confidence interval [CI] 57%, 66%) and shade (26.5%, 95% CI 22%, 31%) were the most frequently reported protection methods. Parents reported higher rates of protection for younger children and children who sunburn easily. CONCLUSIONS: Parents report that a large proportion of white children is protected from sun exposure by one or more methods. Health care providers and educators might encourage the use of all methods of protection, not just sunscreen use, and educate older children to protect themselves from the sun.

Vitamin/mineral supplementation among cancer survivors: 1987 and 1992 National Health Interview Surveys.

The number of cancer survivors in the United States is increasing, but little is known about this population, including its use of vitamin/mineral supplements. We combined data on vitamin/mineral use from the 1987 and 1992 National Health Interview Survey Cancer Epidemiology Supplement (CES) for cancer survivors: persons reporting a diagnosis of cancer other than nonmelanoma skin cancer > 5 yr before their interviews [n = 461 (1987) and 228 (1992)] and persons reporting no history of cancer [n = 20,851 (1987) and 11,186 (1992)]. For both groups, we calculated gender-specific proportions (adjusted for age, race/ethnicity, education, smoking status, and poverty index) for use of multivitamins, vitamins A, C, and E, and calcium during the year before each survey. Supplement use was similar in survivors and persons reporting no history of cancer. Among survivors, calcium use was significantly higher among women (34.9%) than men (13.8%), and vitamin A use was higher among men than women (P < 0.05). Over three-fourths of both groups used multivitamins, and about one-half used vitamin C. No differences were found in vitamin/mineral use between male survivors and men with no cancer history or between female survivors and women with no cancer history. These first nationally representative estimates suggest that persons who have survived cancer and those who report that they never had the disease do not differ appreciably in their use of vitamin/mineral supplements. Results were based on small numbers of survivors, however, and require replication.

The binding of cocaine to cyclodextrins.

Cocaine binds into beta-cyclodextrin, but not detectably into alpha- or gamma-cyclodextrin, in water solution. NMR studies indicate the geometry of the complex, which is confirmed by molecular mechanics calculations and binding studies on cocaine analogues and cyclodextrin dimers.

Diet and lung cancer mortality: a 1987 National Health Interview Survey cohort study.

OBJECTIVES: To study the association between diet and lung cancer mortality in the United States. METHODS: Records from 20,195 participants with usable dietary data in the 1987 National Health Interview Survey were linked to the National Death Index. Baseline diet was assessed with a 59-item food-frequency questionnaire. Food groups (fruits, vegetables, total meat/poultry/fish, red meats, processed meats, dairy products, breakfast cereals, other starches, added fats, and alcohol) were analyzed in cause-specific Cox proportional hazard regression models adjusted for age, gender and smoking. RESULTS: There were 158 deaths from lung cancer (median follow-up 8.5 years). Frequencies of meat/poultry/fish intake (relative risk [RR] (highest compared to lowest quartile) = 2.0; 95% confidence interval [CI] 1.2-3.5, p for trend [p] < 0.027), and red meat intake (RR = 1.6; CI 1.0-2.6, p < 0.014), were positively and significantly associated with lung cancer mortality. Specifically, the red meats, including pork (RR = 1.6; CI 1.0-2.7, p < 0.028), and ground beef (RR = 2.0; CI 1.1-3.5, p < 0.096) were associated with increased risk, although for ground beef the trend was not significant. Dairy products (RR = 0.5; CI 0.3-0.8, p < 0.009) were inversely associated with lung cancer mortality. There was no statistically significant association between intake of fruits and vegetables and lung cancer mortality. CONCLUSIONS: In this nationally representative study, intake of red meats was positively associated with lung cancer mortality while intake of dairy products was inversely associated. While smoking is the major risk for lung cancer mortality, diet may have a contributory role.

The psychiatric emergency service: where we've been and where we're going.

The Psychiatric Emergency Service (PES) has evolved into a separate service with its own space and staff specialized for the handling of psychiatric emergencies. A study of trends in our PES reveals increased need for children's services, issues with managed care and an expansion in the use of the PES as a filter for the mental health system in dealing with substance abuse. Education and research have been added to the missions of the PES and there is strong potential for future development in this area. PESs of the future may be very different, with advances in communication, safety, computerized records and databases. New dilemmas in balancing the patient's right to confidentiality and autonomy against the potential of these advances are bound to occur.

Male pattern baldness and clinical prostate cancer in the epidemiologic follow-up of the first National Health and Nutrition Examination Survey.

Male pattern baldness (MPB) and prostate cancer are common in American males; however, MPB is clinically observable decades earlier. Aging, androgens, and heritability are risk factors for both conditions. We prospectively studied the association between MPB and clinical prostate cancer in a cohort representative of the United States male population. A total of 4,421 men 25-75 years old without a history of prostate cancer were examined for baldness in the Epidemiologic Follow-up Study of the first National Health and Nutrition Examination Survey. Participants were followed from baseline (1971-1974) through 1992. Incident cases of prostate cancer were identified by interviews, medical records, and death certificates. Age-standardized incidence rates and proportional hazards models were used to examine the association between MPB and clinical prostate cancer. Prostate cancer was diagnosed in 214 subjects over 17-21 years of follow-up. The age-standardized incidence of prostate cancer was greater among men with baldness at baseline (17.5 versus 12.5 per 10,000 person-years). The adjusted relative risk for prostate cancer among men with baldness was 1.50 (95% confidence interval, 1.12-2.00) and was similar regardless of the severity of baldness at baseline and was independent of other risk factors, including race and age. MPB seems to be a risk factor for clinical prostate cancer.