Publications by authors named "Benjamin Lane"

31 Publications

Respiratory viruses in pediatric emergency department patients and their family members.

Influenza Other Respir Viruses 2021 01 30;15(1):91-98. Epub 2020 Jul 30.

Environmental Health Sciences Department, Mailman School of Public Health, Columbia University, New York, NY, USA.

Background: Respiratory viral infections account for a substantial fraction of pediatric emergency department (ED) visits. We examined the epidemiological patterns of seven common respiratory viruses in children presenting to EDs with influenza-like illness (ILI). Additionally, we examined the co-occurrence of viral infections in the accompanying adults and risk factors associated with the acquisition of these viruses.

Methods: Nasopharyngeal swab were collected from children seeking medical care for ILI and their accompanying adults (Total N = 1315). Study sites included New York Presbyterian, Bellevue, and Tisch hospitals in New York City. PCR using a respiratory viral panel was conducted, and data on symptoms and medical history were collected.

Results: Respiratory viruses were detected in 399 children (62.25%) and 118 (17.5%) accompanying adults. The most frequent pathogen detected was human rhinovirus (HRV) (28.81%). Co-infection rates were 14.79% in children and 8.47% in adults. Respiratory syncytial virus (RSV) and parainfluenza infections occurred more often in younger children. Influenza and HRV occurred more often in older children. Influenza and coronavirus were mostly isolated in winter and spring, RSV in fall and winter and HRV in fall and spring. Children with HRV were more likely to have history of asthma. Adults with the same virus as their child often accompanied ≤ 2-year-old-positive children and were more likely to be symptomatic compared to adults with different viruses.

Conclusions: Respiratory viruses, while presenting the same suite of symptoms, possess distinct seasonal cycles and affect individuals differently based on a number of identifiable factors, including age and history of asthma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/irv.12789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767945PMC
January 2021

Governance Roles and Capacities of Ministries of Health: A Multidimensional Framework.

Int J Health Policy Manag 2020 Mar 15. Epub 2020 Mar 15.

World Health Organization, Geneva, Switzerland.

The lack of capacity for governance of Ministries of Health (MoHs) is frequently advanced as an explanation for health systems failures in low- and middle-income countries (LMICs). But do we understand what governance capacities MoHs should have? Existing frameworks have not fully captured the dynamic and contextually determined role of MoHs, and there are few frameworks that specifically define capacities for governance. We propose a multidimensional framework of capacities for governance by MoHs that encompasses both the "hard" (, explicit and functional) and "soft" (, tacit, and relational) dimensions of governance, and reflects the diversification of their mandates in the context of the Sustainable Development Goals (SDGs). Four case studies illustrate different aspects of the framework. We hope that the framework will have multiple potential benefits including benchmarking MoH governance capacities, identifying and helping analyze capacity gaps, and guiding strategies to strengthen capacity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.34172/ijhpm.2020.39DOI Listing
March 2020

Active surveillance documents rates of clinical care seeking due to respiratory illness.

Influenza Other Respir Viruses 2020 09 16;14(5):499-506. Epub 2020 May 16.

Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.

Background: Respiratory viral infections are a leading cause of disease worldwide. However, the overall community prevalence of infections has not been properly assessed, as standard surveillance is typically acquired passively among individuals seeking clinical care.

Methods: We conducted a prospective cohort study in which participants provided daily diaries and weekly nasopharyngeal specimens that were tested for respiratory viruses. These data were used to analyze healthcare seeking behavior, compared with cross-sectional ED data and NYC surveillance reports, and used to evaluate biases of medically attended ILI as signal for population respiratory disease and infection.

Results: The likelihood of seeking medical attention was virus-dependent: higher for influenza and metapneumovirus (19%-20%), lower for coronavirus and RSV (4%), and 71% of individuals with self-reported ILI did not seek care and half of medically attended symptomatic manifestations did not meet the criteria for ILI. Only 5% of cohort respiratory virus infections and 21% of influenza infections were medically attended and classifiable as ILI. We estimated 1 ILI event per person/year but multiple respiratory infections per year.

Conclusion: Standard, healthcare-based respiratory surveillance has multiple limitations. Specifically, ILI is an incomplete metric for quantifying respiratory disease, viral respiratory infection, and influenza infection. The prevalence of respiratory viruses, as reported by standard, healthcare-based surveillance, is skewed toward viruses producing more severe symptoms. Active, longitudinal studies are a helpful supplement to standard surveillance, can improve understanding of the overall circulation and burden of respiratory viruses, and can aid development of more robust measures for controlling the spread of these pathogens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/irv.12753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276732PMC
September 2020

Longitudinal active sampling for respiratory viral infections across age groups.

Influenza Other Respir Viruses 2019 05 15;13(3):226-232. Epub 2019 Feb 15.

Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York.

Background: Respiratory viral infections are a major cause of morbidity and mortality worldwide. However, their characterization is incomplete because prevalence estimates are based on syndromic surveillance data. Here, we address this shortcoming through the analysis of infection rates among individuals tested regularly for respiratory viral infections, irrespective of their symptoms.

Methods: We carried out longitudinal sampling and analysis among 214 individuals enrolled at multiple New York City locations from fall 2016 to spring 2018. We combined personal information with weekly nasal swab collection to investigate the prevalence of 18 respiratory viruses among different age groups and to assess risk factors associated with infection susceptibility.

Results: 17.5% of samples were positive for respiratory viruses. Some viruses circulated predominantly during winter, whereas others were found year round. Rhinovirus and coronavirus were most frequently detected. Children registered the highest positivity rates, and adults with daily contacts with children experienced significantly more infections than their counterparts without children.

Conclusion: Respiratory viral infections are widespread among the general population with the majority of individuals presenting multiple infections per year. The observations identify children as the principal source of respiratory infections. These findings motivate further active surveillance and analysis of differences in pathogenicity among respiratory viruses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/irv.12629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468062PMC
May 2019

Asymptomatic Shedding of Respiratory Virus among an Ambulatory Population across Seasons.

mSphere 2018 07 11;3(4). Epub 2018 Jul 11.

Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, USA.

Most observation of human respiratory virus carriage is derived from medical surveillance; however, the infections documented by this surveillance represent only a symptomatic fraction of the total infected population. As the role of asymptomatic infection in respiratory virus transmission is still largely unknown and rates of asymptomatic shedding are not well constrained, it is important to obtain more-precise estimates through alternative sampling methods. We actively recruited participants from among visitors to a New York City tourist attraction. Nasopharyngeal swabs, demographics, and survey information on symptoms, medical history, and recent travel were obtained from 2,685 adults over two seasonal arms. We used multiplex PCR to test swab specimens for a selection of common respiratory viruses. A total of 6.2% of samples (168 individuals) tested positive for at least one virus, with 5.6% testing positive in the summer arm and 7.0% testing positive in the winter arm. Of these, 85 (50.6%) were positive for human rhinovirus (HRV), 65 (38.7%) for coronavirus (CoV), and 18 (10.2%) for other viruses (including adenovirus, human metapneumovirus, influenza virus, and parainfluenza virus). Depending on the definition of symptomatic infection, 65% to 97% of infections were classified as asymptomatic. The best-fit model for prediction of positivity across all viruses included a symptom severity score, Hispanic ethnicity data, and age category, though there were slight differences across the seasonal arms. Though having symptoms is predictive of virus positivity, there are high levels of asymptomatic respiratory virus shedding among the members of an ambulatory population in New York City. Respiratory viruses are common in human populations, causing significant levels of morbidity. Understanding the distribution of these viruses is critical for designing control methods. However, most data available are from medical records and thus predominantly represent symptomatic infections. Estimates for asymptomatic prevalence are sparse and span a broad range. In this study, we aimed to measure more precisely the proportion of infections that are asymptomatic in a general, ambulatory adult population. We recruited participants from a New York City tourist attraction and administered nasal swabs, testing them for adenovirus, coronavirus, human metapneumovirus, rhinovirus, influenza virus, respiratory syncytial virus, and parainfluenza virus. At recruitment, participants completed surveys on demographics and symptomology. Analysis of these data indicated that over 6% of participants tested positive for shedding of respiratory virus. While participants who tested positive were more likely to report symptoms than those who did not, over half of participants who tested positive were asymptomatic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSphere.00249-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041500PMC
July 2018

Observation of an optical spring with a beam splitter.

Opt Lett 2018 May;43(9):2193-2196

We present the experimental observation of an optical spring without the use of an optical cavity. The optical spring is produced by interference at a beam splitter and, in principle, does not have the damping force associated with optical springs created in detuned cavities. The experiment consists of a Michelson-Sagnac interferometer (with no recycling cavities) with a partially reflective GaAs microresonator as the beam splitter that produces the optical spring. Our experimental measurements at input powers of up to 360 mW show the shift of the optical spring frequency as a function of power and are in excellent agreement with theoretical predictions. In addition, we show that the optical spring is able to keep the interferometer stable and locked without the use of external feedback.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/OL.43.002193DOI Listing
May 2018

Asymptomatic Summertime Shedding of Respiratory Viruses.

J Infect Dis 2018 03;217(7):1074-1077

Sackler Institute of Comparative Genomics, American Museum of Natural History, New York, New York.

To determine rates of both symptomatic and asymptomatic infection among ambulatory adults, we collected nasopharyngeal swab specimens, demographic characteristics, and survey information from 1477 adult visitors to a New York City tourist attraction during April-July 2016. Multiplex polymerase chain reaction analysis was used to identify specimens positive for common respiratory viruses. A total of 7.2% of samples tested positive for respiratory viruses; among positive samples, 71.0% contained rhinovirus, and 21.5% contained coronavirus. Influenza virus, respiratory syncytial virus, and parainfluenza virus were also detected. Depending on symptomatologic definition, 57.7%-93.3% of positive samples were asymptomatic. These findings indicate that significant levels of asymptomatic respiratory viral shedding exist during summer among the ambulatory adult population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jix685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7107397PMC
March 2018

Randomized Comparison of 3 High-Level Disinfection and Sterilization Procedures for Duodenoscopes.

Gastroenterology 2017 10 13;153(4):1018-1025. Epub 2017 Jul 13.

Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. Electronic address:

Background And Aims: Duodenoscopes have been implicated in the transmission of multidrug-resistant organisms (MDRO). We compared the frequency of duodenoscope contamination with MDRO or any other bacteria after disinfection or sterilization by 3 different methods.

Methods: We performed a single-center prospective randomized study in which duodenoscopes were randomly reprocessed by standard high-level disinfection (sHLD), double high-level disinfection (dHLD), or standard high-level disinfection followed by ethylene oxide gas sterilization (HLD/ETO). Samples were collected from the elevator mechanism and working channel of each duodenoscope and cultured before use. The primary outcome was the proportion of duodenoscopes with an elevator mechanism or working channel culture showing 1 or more MDRO; secondary outcomes included the frequency of duodenoscope contamination with more than 0 and 10 or more colony-forming units (CFU) of aerobic bacterial growth on either sampling location.

Results: After 3 months of enrollment, the study was closed because of the futility; we did not observe sufficient events to evaluate the primary outcome. Among 541 duodenoscope culture events, 516 were included in the final analysis. No duodenoscope culture in any group was positive for MDRO. Bacterial growth of more than 0 CFU was noted in 16.1% duodenoscopes in the sHLD group, 16.0% in the dHLD group, and 22.5% in the HLD/ETO group (P = .21). Bacterial growth or 10 or more CFU was noted in 2.3% of duodenoscopes in the sHLD group, 4.1% in the dHLD group, and 4.2% in the HLD/ETO group (P = .36). MRDOs were cultured from 3.2% of pre-procedure rectal swabs and 2.5% of duodenal aspirates.

Conclusions: In a comparison of duodenoscopes reprocessed by sHLD, dHLD, or HLD/ETO, we found no significant differences between groups for MDRO or bacteria contamination. Enhanced disinfection methods (dHLD or HLD/ETO) did not provide additional protection against contamination. However, insufficient events occurred to assess our primary study end-point. ClinicalTrials.gov no: NCT02611648.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2017.06.052DOI Listing
October 2017

Adenosine Triphosphate Quantification Correlates Poorly with Microbial Contamination of Duodenoscopes.

Infect Control Hosp Epidemiol 2017 06 17;38(6):678-684. Epub 2017 Apr 17.

1Division of Infection Control/Hospital Epidemiology,Silverman Institute of Health Care Quality & Safety,Beth Israel Deaconess Medical Center,Boston,Massachusetts.

OBJECTIVE The aim of this study was to quantify the correlation between adenosine triphosphate (ATP) measurements and bacterial cultures from duodenoscopes for evaluation of contamination following high-level disinfection. DESIGN Duodenoscopes used for any intended endoscopic retrograde cholangiopancreatography (ERCP) procedure were included. Microbiologic and ATP data were collected concomitantly and in the same manner from ERCP duodenoscopes. SETTING A high-volume endoscopy unit at a tertiary referral acute-care facility. METHODS Duodenoscopes were sampled for ATP and bacterial contamination in a contemporaneous and highly standardized fashion using a "flush-brush-flush" method for the working channel (WC) and a dry flocked swab for the elevator mechanism (EM). Specimens were processed for any aerobic bacterial growth (colony-forming units, CFU). Growth of CFU>0 and ATP relative light unit (RLU)>0 was considered a contaminated result. Frequency of discord between among WC and EM measurements were calculated using 2×2 contingency tables. The Spearman correlation coefficient was used to calculate the relatedness of bacterial contamination and ATP as continuous measurements. RESULTS The Spearman correlation coefficient did not demonstrate significant relatedness between ATP and CFU for either a WC or EM site. Among 390 duodenoscope sampling events, ATP and CFU assessments of contamination were discordant in 82 of 390 WC measurements (21%) and 331 of 390 of EM measurements (84.9%). The EM was frequently and markedly positive by ATP measurement. CONCLUSION ATP measurements correlate poorly with a microbiologic standard assessing duodenoscope contamination, particularly for EM sampling. ATP may reflect biological material other than nonviable aerobic bacteria and may not serve as an adequate marker of bacterial contamination. Infect Control Hosp Epidemiol 2017;38:678-684.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/ice.2017.58DOI Listing
June 2017

Competency to stand trial evaluations in a multicultural population: Associations between psychiatric, demographic, and legal factors.

Int J Law Psychiatry 2016 Jul-Aug;47:79-85. Epub 2016 Apr 13.

Department of Psychiatry, Mount Sinai-Roosevelt Hospital, 1111Amsterdam Avenue, New York, NY 10025, USA.

Data were examined from an archival sample of Competency to Stand Trial (CST) reports of 200 consecutive New York City pre-trial defendants evaluated over a five-month period. Approximately a fourth of defendants in the present study were immigrants; many required the assistance of interpreters. The examiners conducting the CST evaluation diagnosed approximately half of the defendants with a primary diagnosis of a psychotic disorder and deemed over half not competent. Examiners reached the same conclusion about competency in 96% of cases, about the presence of a psychotic disorder in 91% of cases, and affective disorder in 85% of cases. No significant differences between psychologists and psychiatrists were found for rates of competency/incompetency opinions. Compared to those deemed competent, defendants deemed not competent had significantly higher rates of prior psychiatric hospitalization and diagnosis of psychotic illness at the time of the CST evaluation but lower rates of reported substance abuse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijlp.2016.02.039DOI Listing
January 2018

Base pair opening in a deoxynucleotide duplex containing a cis-syn thymine cyclobutane dimer lesion.

Biochemistry 2013 Dec 11;52(51):9275-85. Epub 2013 Dec 11.

Department of Chemistry, Mount Holyoke College , South Hadley, Massachusetts 01075, United States.

The cis-syn thymine cyclobutane dimer is a DNA photoproduct implicated in skin cancer. We compared the stability of individual base pairs in thymine dimer-containing duplexes to undamaged parent 10-mer duplexes. UV melting thermodynamic measurements, CD spectroscopy, and 2D NOESY NMR spectroscopy confirm that the thymine dimer lesion is locally and moderately destabilizing within an overall B-form duplex conformation. We measured the rates of exchange of individual imino protons by NMR using magnetization transfer from water and determined the equilibrium constant for the opening of each base pair K(op). In the normal duplex K(op) decreases from the frayed ends of the duplex toward the center, such that the central TA pair is the most stable with a K(op) of 8 × 10⁻⁷. In contrast, base pair opening at the 5'T of the thymine dimer is facile. The 5'T of the dimer has the largest equilibrium constant (K(op) = 3 × 10⁻⁴) in its duplex, considerably larger than even the frayed penultimate base pairs. Notably, base pairing by the 3'T of the dimer is much more stable than by the 5'T, indicating that the predominant opening mechanism for the thymine dimer lesion is not likely to be flipping out into solution as a single unit. The dimer asymmetrically affects the stability of the duplex in its vicinity, destabilizing base pairing on its 5' side more than on the 3' side. The striking differences in base pair opening between parent and dimer duplexes occur independently of the duplex-single strand melting transitions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/bi401312rDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3912563PMC
December 2013

Flight demonstration of a milliarcsecond pointing system for direct exoplanet imaging.

Appl Opt 2012 Oct;51(29):7069-79

Astronomy Department, Boston University, Boston, Massachusetts 02215, USA.

We present flight results from the optical pointing control system onboard the Planetary Imaging Concept Testbed Using a Rocket Experiment (PICTURE) sounding rocket. PICTURE (NASA mission number: 36.225 UG) was launched on 8 October 2011, from White Sands Missile Range. It attempted to directly image the exozodiacal dust disk of ϵ Eridani (K2V, 3.22 pc) down to an inner radius of 1.5 AU using a visible nulling coronagraph. The rocket attitude control system (ACS) provided 627 milliarcsecond (mas) RMS body pointing (~2'' peak-to-valley). The PICTURE fine pointing system (FPS) successfully stabilized the telescope beam to 5.1 mas (0.02λ/D) RMS using an angle tracker camera and fast steering mirror. This level of pointing stability is comparable to that of the Hubble Space Telescope. We present the hardware design of the FPS, a description of the limiting noise sources and a power spectral density analysis of the FPS and rocket ACS in-flight performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/AO.51.007069DOI Listing
October 2012

Interpixel crosstalk in Teledyne Imaging Sensors H4RG-10 detectors.

Appl Opt 2012 May;51(15):2877-87

United States Naval Observatory, Washington, DC 20392, USA.

Complementary metal-oxide semiconductor (CMOS)-hybrid arrays have become competitive optical detectors for use in ground- and space-based astronomy. Interpixel capacitance (IPC) is one source of error that appears in most CMOS arrays. In this paper, we use a single-pixel-reset method to model IPC. We combine this IPC model with a model for charge diffusion to estimate the total crosstalk on H4RG-10 arrays. Finally, we compare our model results to 55Fe data obtained using an astrometric camera built to test the H4RG-10 B0 generation detectors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/AO.51.002877DOI Listing
May 2012

Hidden in plain sight: subtle effects of the 8-oxoguanine lesion on the structure, dynamics, and thermodynamics of a 15-base pair oligodeoxynucleotide duplex.

Biochemistry 2011 Oct 8;50(39):8463-77. Epub 2011 Sep 8.

Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, United States.

The base lesion 8-oxoguanine is formed readily by oxidation of DNA, potentially leading to G → T transversion mutations. Despite the apparent similarity of 8-oxoguanine-cytosine base pairs to normal guanine-cytosine base pairs, cellular base excision repair systems effectively recognize the lesion base. Here we apply several techniques to examine a single 8-oxoguanine lesion at the center of a nonpalindromic 15-mer duplex oligonucleotide in an effort to determine what, if anything, distinguishes an 8-oxoguanine-cytosine (8oxoG-C) base pair from a normal base pair. The lesion duplex is globally almost indistinguishable from the unmodified parent duplex using circular dichroism spectroscopy and ultraviolet melting thermodynamics. The DNA mismatch-detecting photocleavage agent Rh(bpy)(2)chrysi(3+) cleaves only weakly and nonspecifically, revealing that the 8oxoG-C pair is locally stable at the level of the individual base pairs. Nuclear magnetic resonance spectra are also consistent with a well-conserved B-form duplex structure. In the two-dimensional nuclear Overhauser effect spectra, base-sugar and imino-imino cross-peaks are strikingly similar between parent and lesion duplexes. Changes in chemical shift due to the 8oxoG lesion are localized to its complementary cytosine and to the 2-3 bp immediately flanking the lesion on the lesion strand. Residues further removed from the lesion are shown to be unperturbed by its presence. Notably, imino exchange experiments indicate that the 8-oxoguanine-cytosine pair is strong and stable, with an apparent equilibrium constant for opening equal to that of other internal guanine-cytosine base pairs, on the order of 10(-6). This collection of experiments shows that the 8-oxoguanine-cytosine base pair is incredibly stable and similar to the native pair.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/bi201007tDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188433PMC
October 2011

OPD measurement and dispersion reduction in a monolithic interferometer.

Opt Express 2010 Aug;18(16):17542-7

Center for Space Physics, Boston University, 725 Commonwealth Avenue, Boston, MA 02215, USA.

We describe a white light fringe scanning and pupil bisecting method of measuring the optical path difference (OPD) between arms of a monolithic nulling interferometer that is designed to enable direct imaging of planetary companions and the environments around nearby stars. This measurement is used to determine the differential thicknesses of optically contacted compensator plates used to reduce OPD, which can drastically impair the optic's performance in broadband light. By making this correction, we were able to reduce the initial OPD from 949+/-44 nm to 63+/-10 nm. In the absence of any other asymmetries that can compromise the null, such a correction corresponds to an increase in an R-band (lambda(c) = 648 nm) nulling bandpass from monochromatic to 25%.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/OE.18.017542DOI Listing
August 2010

Pyrazolone based TGFbetaR1 kinase inhibitors.

Bioorg Med Chem Lett 2010 Jan 29;20(1):326-9. Epub 2009 Oct 29.

Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.

Interruption of TGFbeta signaling through inhibition of the TGFbetaR1 kinase domain may prove to have beneficial effect in both fibrotic and oncological diseases. Herein we describe the SAR of a novel series of TGFbetaR1 kinase inhibitors containing a pyrazolone core. Most TGFbetaR1 kinase inhibitors described to date contain a core five-membered ring bearing N as H-bond acceptor. Described herein is a novel strategy to replace the core structure with pyrazolone ring, in which the carbonyl group is designed as an H-bond acceptor to interact with catalytic Lys 232.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2009.10.108DOI Listing
January 2010

Monolithic achromatic nulling interference coronagraph: design and performance.

Appl Opt 2009 Sep;48(26):4963-77

Center for Space Physics, Boston University, 725 Commonwealth Avenue, Boston, Massachusetts 02215, USA.

We present the design of the monolithic achromatic nulling interference coronagraph (MANIC), a nulling interferometer consisting of optically contacted prisms and a symmetric beam splitter. The optic is designed to enable the direct detection of nearby Jupiter-like exoplanets, and may be extended to enable Earth-like system detection. The monolithic nature of the optic improves on the current state-of-the-art in nulling interferometers by providing built-in alignment and stability, as well as a reduction in size and mass. These qualities make the MANIC extremely robust and simple to integrate, and an excellent candidate for space-based applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/AO.48.004963DOI Listing
September 2009

Catalytic C-H arylation of SEM-protected azoles with palladium complexes of NHCs and phosphines.

Org Lett 2006 May;8(10):1979-82

Department of Chemistry, Columbia University, New York, New York 10027, USA.

[reaction: see text] The synthesis and catalytic evaluation of palladium complexes containing imidazolyl carbene ligand of varying steric and electronic properties is reported. These complexes catalyze the efficient C-H arylation of SEM-protected azole heteroarenes and thus provide a good method for preparation of a wide range of arylated free (NH)-azoles including pyrroles, indoles, imidazoles, and imidazo[1,2-a]pyridines. The reaction is operationally simple; the complexes are insensitive to moisture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ol053021cDOI Listing
May 2006

Rapamycin analogs with reduced systemic exposure.

Bioorg Med Chem Lett 2005 Dec 26;15(23):5340-3. Epub 2005 Sep 26.

Abbott Laboratories, Global Pharmaceutical Research and Development, Abbott Park, IL 60064, USA.

The synthesis and biological activities of rapamycin (I) analogs modified at the C-40 position are reported. Emphasis placed on compounds that potentially have an improved safety profile on account of their shorter in vivo half-life when compared with rapamycin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2005.06.106DOI Listing
December 2005

Antidiabetic activity of passive nonsteroidal glucocorticoid receptor modulators.

J Med Chem 2005 Aug;48(16):5295-304

Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Department 4CB, Room L-14, Building AP-10, Abbott Park, IL 60064-6098, USA.

Much has been learned about the consequences of glucocorticoid receptor antagonism by studying steroidal active antagonists such as RU-38486 (1). In the liver glucocorticoid receptor antagonism suppresses hepatic glucose production decreasing plasma glucose levels; however, extrahepatic antagonism produces several undesirable side effects including activation of the hypothalamic pituitary adrenal axis. A series of nonsteroidal passive N-(3-dibenzylamino-2-alkyl-phenyl)-methanesulfonamide glucocorticoid receptor modulators was discovered. Liver selective and systemically available members of this series were found and characterized in diabetes and side effect rodent models. A highly liver selective member of this series, acid 14, shows efficacy in the ob/ob model of diabetes. It lowers plasma glucose, cholesterol, and free fatty acid concentrations and reduces the rate of body weight gain. The structurally related systemically available passive modulator 12 lowers glucose, HbA(1c), triglyceride, free fatty acid, and cholesterol levels. Interestingly, it did not acutely activate the hypothalamic pituitary adrenal axis in unstressed CD-1 mice or have the abortive effects observed with 1. These results indicate that passive GR antagonists may have utility as antidiabetic agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm050205oDOI Listing
August 2005

Direct palladium-catalyzed C-2 and C-3 arylation of indoles: a mechanistic rationale for regioselectivity.

J Am Chem Soc 2005 Jun;127(22):8050-7

Department of Chemistry, Columbia University, 3000 Broadway, New York, New York 10027, USA.

We have recently developed palladium-catalyzed methods for direct arylation of indoles (and other azoles) wherein high C-2 selectivity was observed for both free (NH)-indole and (NR)-indole. To provide a rationale for the observed selectivity ("nonelectrophilic" regioselectivity), mechanistic studies were conducted, using the phenylation of 1-methylindole as a model system. The reaction order was determined for iodobenzene (zero order), indole (first order), and the catalyst (first order). These kinetic studies, together with the Hammett plot, provided a strong support for the electrophilic palladation pathway. In addition, the kinetic isotope effect (KIE(H/D)) was determined for both C-2 and C-3 positions. A surprisingly large value of 1.6 was found for the C-3 position where the substitution does not occur (secondary KIE), while a smaller value of 1.2 was found at C-2 (apparent primary KIE). On the basis of these findings, a mechanistic interpretation is presented that features an electrophilic palladation of indole, accompanied by a 1,2-migration of an intermediate palladium species. This paradigm was used to design new catalytic conditions for the C-3 arylation of indole. In case of free (NH)-indole, regioselectivity of the arylation reaction (C-2 versus C-3) was achieved by the choice of magnesium base.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ja043273tDOI Listing
June 2005

Direct C-arylation of free (NH)-indoles and pyrroles catalyzed by Ar-Rh(III) complexes assembled in situ.

J Am Chem Soc 2005 Apr;127(14):4996-7

Department of Chemistry, Columbia University, 3000 Broadway, New York, New York 10027, USA.

Ar-Rh(III) pivalate complexes assembled in situ from the reaction of [RhCl(coe)2]2 (coe = cis-cyclooctene), [p-(CF3)C6H4]3P, and CsOPiv effectively catalyzed the direct C-arylation of free (NH)-indoles and (NH)-pyrroles in good yields and with high regioselectivity. The reaction displayed excellent functional group compatibility and low moisture sensitivity. Kinetics studies support a mechanism involving phosphine displacement by indole in complex 2 (resting state of the catalyst), followed by a rate-limiting C-H bond metalation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ja050279pDOI Listing
April 2005

Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes.

J Pharmacol Exp Ther 2005 Jul 22;314(1):191-200. Epub 2005 Mar 22.

Department of Metabolic Disease Research, Abbott Laboratories, R47M, AP10-111, 100 Abbott Park Rd., Abbott Park, IL 60064, USA.

Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity. A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.104.081257DOI Listing
July 2005

Direct C-H bond arylation: selective palladium-catalyzed C2-arylation of N-substituted indoles.

Org Lett 2004 Aug;6(17):2897-900

Department of Chemistry, Columbia University, 3000 Broadway, New York, New York 10027, USA.

We present a new, practical method by which N-substituted indoles may be selectively arylated in the C2-position with good yields, low catalyst loadings, and a high degree of functional group tolerance. Our investigation found that two competitive processes, namely, the desired cross-coupling and biphenyl formation, were operative in this reaction. A simple kinetic model was formulated that proved to be instructive and provided useful guidelines for reaction optimization; the approach described within may prove to be useful in other catalytic cross-coupling processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ol0490072DOI Listing
August 2004

Managing the megacity for global sustainability: the new york metropolitan region as an urban biosphere reserve.

Ann N Y Acad Sci 2004 Jun;1023:125-41

CUBES, Earth Institute at Columbia University, 2910 Broadway, Hogan Hall B-16, New York, NY 10027, USA.

The UNESCO World Network of Biosphere Reserves (WNBR), while not originally conceived to include urban areas, was intended to include sites representing all significant ecosystems with the goal of support for sustainable development locally and globally. Drawing on the example of the New York Metropolitan Region (NYMR), which has a population of 21.4 million, it is argued here that the eventual inclusion of the largest of the world's cities in WNBR not only is within the logic of the biosphere reserve concept, but would also benefit the network and its goals. The ecological significance of the NYMR, its role as a driver for global environmental change, as well as the efforts under way in the city to improve urban environmental management and governance are all examined. Potential added value to the WNBR of including megacities such as the NYMR is considered, in particular, regarding the sharing of best practices, lessons learned, and the strengthening of links between megacities and their global natural resource bases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1196/annals.1319.005DOI Listing
June 2004

Comparison of measurements of the outer scale of turbulence by three different techniques.

Appl Opt 2004 Apr;43(11):2316-24

Unité Mixte de Recherche 6525 Astrophysique, Université de Nice-Sophia Antipolis, Parc Valrose, 06108 Nice 2, France.

We have made simultaneous and nearly simultaneous measurements of L0, the outer scale of turbulence, at the Palomar Observatory by using three techniques: angle-of-arrival covariance measurements with the Generalized Seeing Monitor (GSM), differential-image-motion measurements with the adaptive-optics system on the Hale 5-m telescope, and fringe speed measurements with the Palomar Testbed Interferometer (PTI). The three techniques give consistent results, an outer scale of approximately 10-20 m, despite the fact that the spatial scales of the three instruments vary from 1 m for the GSM to 100 m for the PTI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/ao.43.002316DOI Listing
April 2004

Metal-catalyzed epoxidations of alkenes with hydrogen peroxide.

Chem Rev 2003 Jul;103(7):2457-73

Department of Chemistry, Texas A & M University, P.O. Box 30012, College Station, Texas 77842-3012, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/cr020471zDOI Listing
July 2003

Nonsteroidal selective glucocorticoid modulators: the effect of C-10 substitution on receptor selectivity and functional potency of 5-allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines.

J Med Chem 2003 Mar;46(6):1016-30

Immunologic Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6061, USA. phil.r.kym@ abbott.com

The preparation and characterization of a series of C-10 substituted 5-allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines as a novel class of selective ligands for the glucocorticoid receptor is described. Substitution at the C-10 position of the tetracyclic core with linear, two-atom appendages (OCH(3), OCF(2)H, NHMe, SMe, CH=CH(2), Ctbd1;CH, CH(2)OH) provided molecules of high affinity (K(i) = 2-8 nM) for the human glucocorticoid receptor (hGR) with limited cross-reactivity with other steroid receptors (PR, MR, AR, ER). Optimal analogues showed slightly less potent but highly efficacious E-selectin repression with reduced levels of GRE activation efficacy in reporter gene assays relative to prednisolone. Preliminary SAR of analogues containing substitution at the C-9 and C-10 positions identified the 9-OH, 10-OMe analogue 50 and the 9-OH, 10-Cl analogue 58 as compounds that demonstrated potent, GR-mediated inhibition in a conconavalin A stimulated T-cell proliferation assay in both rodent and human whole blood monocytes. When evaluated for their in vivo effects in carrageenan-induced paw edema in rats, 50, 58, and 10-OCF(2)H analogue 35 showed dose-dependent anti-inflammatory effects (50, ED(50) = 16 mg/kg; 58, ED(50) = 15 mg/kg; 35, ED(50) = 21 mg/kg vs ED(50) = 15 mg/kg for 18 and ED(50) = 4 mg/kg for prednisolone).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm020335mDOI Listing
March 2003