The Chemical Space Project

One of the simplest questions that can be asked about molecular diversity is how many organic molecules are possible in total? To answer this question, my research group has computationally enumerated all possible organic molecules up to a certain size to gain an unbiased insight into the entire chemical space. Our latest database, GDB-17, contains 166.4 billion molecules of up to 17 atoms of C, N, O, S, and halogens, by far the largest small molecule database reported to date. Molecules allowed by valency rules but unstable or nonsynthesizable due to strained topologies or reactive functional groups were not considered, which reduced the enumeration by at least 10 orders of magnitude and was essential to arrive at a manageable database size. Despite these restrictions, GDB-17 is highly relevant with respect to known molecules. Beyond enumeration, understanding and exploiting GDBs (generated databases) led us to develop methods for virtual screening and visualization of very large databases in the form of a “periodic system of molecules” comprising six different fingerprint spaces, with web-browsers for nearest neighbor searches, and the MQN- and SMIfp-Mapplet application for exploring color-coded principal component maps of GDB and other large databases. Proof-of-concept applications of GDB for drug discovery were realized by combining virtual screening with chemical synthesis and activity testing for neurotransmitter receptor and transporter ligands. One surprising lesson from using GDB for drug analog searches is the incredible depth of chemical space, that is, the fact that millions of very close analogs of any molecule can be readily identified by nearest-neighbor searches in the MQN-space of the various GDBs. The chemical space project has opened an unprecedented door on chemical diversity. Ongoing and yet unmet challenges concern enumerating molecules beyond 17 atoms and synthesizing GDB molecules with innovative scaffolds and pharmacophores.

[Pilot Project: Improved Lung Deposition via a New Nasal Inhalation Procedure].

INTRODUCTION Inhaled drugs can only be effective if they reach the middle and small airways. This study introduces a system that combines a trans-nasal application of aerosols with noninvasive pressure support ventilation. METHODS In a pilot study, 7 COPD patients with GOLD stages II and III inhaled a radiolabeled marker dissolved in water via a trans-nasal route. The mean aerosol particle size was 5.5 µm. Each patient took part in two inhalation sessions that included two application methods and were at least 70 hours apart. During the first session ("passive method"), the patient inhaled the aerosol through an open tube system. The second session ("active method") included pressure support ventilation during the inhalation process. A gamma camera and planar scintigraphy was used to determine the distribution of aerosol particles in the patient's body and lung. RESULTS The pressure supported inhalation ("active method") results in an increased aerosol lung deposition compared to the passive method. Above all, we could demonstrate deposition in the lung periphery with relatively large aerosol particles (5.5 µm). DISCUSSION The results prove that the combination of trans-nasal inhalation with noninvasive pressure support ventilation leads to significantly increased particle deposition in the lung.

Adjustable Art Table Project

An adjustable art table was designed for the artists at Passion Works Studio to fulfill a need for a wheelchair-friendly art table. The client desired that the table be sturdy, not electronic and can be used by multiple users. In response, a mechanical approach was taken and various raising devices were explored. A mechanical height adjustment would make for a more stable table and would not require any electricity or motor to adjust. The table also was built with a large, smooth tabletop designed specifically for multiple users making art. The highlight feature is the height adjustment which allows the table to adjust between 29 and 42.5 inches. The table requires just one person to raise, and two people to lower. To raise the table, an individual only needs to unlock the legs and then press in a button to activate the gas springs, which raise the table. Once the table is set to the desired height, the table can lock into place securely. To lower the table, one person must activate the gas springs and push down simultaneously with another person pushing down on the other side of the table. There is enough room for three people, depending on the size of the wheelchairs. With no wheelchairs, as many as six people can use the table. Therefore, the specifications were met, since it raises and lowers within the desired range, and it provides a solid surface for multiple users to do art work.

Concordance between medical records and personal interview in ascertaining breast cancer and diabetes status: Analysis of the south Texas women's health project

Accurate ascertainment of risk factors and disease status is vital in public health research for proper classification of research subjects. The two most common ways of obtaining this data is by self-report and review of medical records (MRs). South Texas Women’s Health Project was a case-control study looking at interrelationships between hormones, diet, and body size and breast cancer among Hispanic women 30-79 years of age. History of breast cancer, diabetes mellitus (DM) and use of DM medications was ascertained from a personal interview. At the time of interview, the subject identified her major health care providers and signed the medical records release form, which was sent to the designated providers. The MRs were reviewed to confirm information obtained from the interview.^ Aim of this study was to determine the sensitivity and specificity between MRs and personal interview in diagnosis of breast cancer, DM and DM treatment. We also wanted to assess how successful our low-cost approach was in obtaining pertinent MRs and what factors influenced the quality of MR or interview data. Study sample was 721 women with both self-report and MR data available by June 2007. Overall response rate for MR requests was 74.5%. MRs were 80.9% sensitive and 100% specific in confirming breast cancer status. Prevalence of DM was 22.7% from the interviews and 16% from MRs. MRs did not provide definite information about DM status of 53.6% subjects. Sensitivity and specificity of MRs for DM status was 88.9% and 90.4% respectively. Disagreement on DM status from the two sources was seen in 15.9% subjects. This discordance was more common among older subjects, those who were married and were predominantly Spanish speaking. Income and level of education did not have a statistically significantly association with this disagreement.^ Both self-report and MRs underestimate the prevalence of DM. Relying solely on MRs leads to greater misclassification than relying on self-report data. MRs have good to excellent specificity and thus serve as a good tool to confirm information obtained from self-report. Self-report and MRs should be used in a complementary manner for accurate assessment of DM and breast cancer status.^

Endemic tuberculosis, the homeless, and public transportation: A merging of geographical information systems surveillance and the Houston Tuberculosis Initiative Surveillance project

To reach the goals established by the Institute of Medicine (IOM) and the Centers for Disease Control's (CDC) STOP TB USA, measures must be taken to curtail a future peak in Tuberculosis (TB) incidence and speed the currently stagnant rate of TB elimination. Both efforts will require, at minimum, the consideration and understanding of the third dimension of TB transmission: the location-based spread of an airborne pathogen among persons known and unknown to each other. This consideration will require an elucidation of the areas within the U.S. that have endemic TB. The Houston Tuberculosis Initiative (HTI) was a population-based active surveillance of confirmed Houston/Harris County TB cases from 1995–2004. Strengths in this dataset include the molecular characterization of laboratory confirmed cases, the collection of geographic locations (including home addresses) frequented by cases, and the HTI time period that parallels a decline in TB incidence in the United States (U.S.). The HTI dataset was used in this secondary data analysis to implement a GIS analysis of TB cases, the locations frequented by cases, and their association with risk factors associated with TB transmission. ^ This study reports, for the first time, the incidence of TB among the homeless in Houston, Texas. The homeless are an at-risk population for TB disease, yet they are also a population whose TB incidence has been unknown and unreported due to their non-enumeration. The first section of this dissertation identifies local areas in Houston with endemic TB disease. Many Houston TB cases who reported living in these endemic areas also share the TB risk factor of current or recent homelessness. Merging the 2004–2005 Houston enumeration of the homeless with historical HTI surveillance data of TB cases in Houston enabled this first-time report of TB risk among the homeless in Houston. The homeless were more likely to be US-born, belong to a genotypic cluster, and belong to a cluster of a larger size. The calculated average incidence among homeless persons was 411/100,000, compared to 9.5/100,000 among housed. These alarming rates are not driven by a co-infection but by social determinants. The unsheltered persons were hospitalized more days and required more follow-up time by staff than those who reported a steady housing situation. The homeless are a specific example of the increased targeting of prevention dollars that could occur if TB rates were reported for specific areas with known health disparities rather than as a generalized rate normalized over a diverse population. ^ It has been estimated that 27% of Houstonians use public transportation. The city layout allows bus routes to run like veins connecting even the most diverse of populations within the metropolitan area. Secondary data analysis of frequent bus use (defined as riding a route weekly) among TB cases was assessed for its relationship with known TB risk factors. The spatial distribution of genotypic clusters associated with bus use was assessed, along with the reported routes and epidemiologic-links among cases belonging to the identified clusters. ^ TB cases who reported frequent bus use were more likely to have demographic and social risk factors associated with poverty, immune suppression and health disparities. An equal proportion of bus riders and non-bus riders were cultured for Mycobacterium tuberculosis, yet 75% of bus riders were genotypically clustered, indicating recent transmission, compared to 56% of non-bus riders (OR=2.4, 95%CI(2.0, 2.8), p<0.001). Bus riders had a mean cluster size of 50.14 vs. 28.9 (p<0.001). Second order spatial analysis of clustered fingerprint 2 (n=122), a Beijing family cluster, revealed geographic clustering among cases based on their report of bus use. Univariate and multivariate analysis of routes reported by cases belonging to these clusters found that 10 of the 14 clusters were associated with use. Individual Metro routes, including one route servicing the local hospitals, were found to be risk factors for belonging to a cluster shown to be endemic in Houston. The routes themselves geographically connect the census tracts previously identified as having endemic TB. 78% (15/23) of Houston Metro routes investigated had one or more print groups reporting frequent use for every HTI study year. We present data on three specific but clonally related print groups and show that bus-use is clustered in time by route and is the only known link between cases in one of the three prints: print 22. (Abstract shortened by UMI.)^

Grain size analysis on CRP sediment cores from the Ross Sea, Antarctica

The upper 1200 m of pre-Pliocene sediment recovered by Cape Roberts Project (CRP) drilling off the Victoria Land coast of Antarctica between 1997-1999 has been subdivided into 54 unconformity-bound stratigraphic sequences, spanning the period c. 32 to 17 Ma. The sequences are recognised on the basis of the cyclical vertical stacking of their constituent lithofacies, which are enclosed by erosion surfaces produced during the grounding of the advancing ice margin onto the sea floor. Each sequence represents deposition in a range of offshore shelf to coastal glacimarine sedimentary environments during oscillations in the ice margin across the Western Ross Sea shelf, and coeval fluctuations in water depth. This paper applies spectral analysis techniques to depth- and time-series of sediment grain size (500 samples) for intervals of the core with adequate chronological data. Time series analysis of 0.5-l.0m-spaced grainsize data spanning sequences 9-11 (CRP-2/2A) and sequences 1-7 (CRP-3) suggests that the length of individual sequences correspond to Milankovitch frequencies, probably 41 k.y., but possibly as low as 100 k.y. Higher frequency periodic components at 23 k.y. (orbital precession) and 15-10 k.y. (sub-orbital) are recognised at the intrasequence-scale, and may represent climatic cycles akin to the ice rafting episodes described in the North Atlantic Ocean during the Quaternary. The cyclicity recorded by glacimarine sequences in CRP core provides direct evidence from the periphery of Antarctica for orbital oscillations in the size of the Oligocene-Early Miocene East Antarctic Ice Sheet.

Grain size analysis of sediment core CRP-3 from the Ross Sea, Antarctica

Grain-size analyses by sieve and Sedigraph are presented for 115 samples of core from CRP-3, 12 km off the coast of south Victoria Land. The data provide a useful check on visual core descriptions. The geographic setting for the strata sampled, some 790 m of early Oligocene nearshore marine sediments with a persistent glacial influence, is reviewed, and sediment textures interpreted in that context. Sand textures from the CRP-3 samples in the lower part of the core suggest that deposition was initially primarily wave-dominated, but that at times the influence of the waves was over-ridden by episodes of rapid sedimentation. Sedimentary cycles, recognised in the visual description of the core above 485 mbsf, show an increasing proportion of mudstone in the middle of each cycle above 330 mbsf that is interpreted to record periodic sedimentation in deeper water. Sandstone textures in the lower and upper parts of each cycle are interpreted to record departure from and return to shoreface deposition with changes in sea level. Mudstone textures above 176 mbsf indicate sedimentation below wave base. Many of the textures in both sand and mud samples show the coarse 'tail' characteristic of ice-rafted debris, but others do not, indicating ice-free periods. Many sandstones below c. 200 mbsf have virtually no silt, but significant amounts of clay (6 to 17%) that is thought to be of post-depositional origin.

Grain size analysis of sediment coring site CRP-2 from the Ross Sea, Antarctica

The purpose of this note is to present results of grain size analyses from 118 samples of the CRP-2/2A core using sieve and Sedigraph techniques. The samples were selected to represent the range of facies encountered, and tend to become more widely spaced with depth. Fifteen came from the upper 27 m of Quaternary and Pliocene sediments, 62 from the early Miocene-late Oligocene strata (27 to 307 mbsf), and 41 from the early Oligocene strata beneath (307 to 624 mbsf). The results are intended to provide reference data for lithological descriptions in the core logs (Cape Roberts Science Team, 1999), and to help with facies interpretation. The analytical technique used for determining size frequency of the sand fraction in our samples (sieving) is simple, physical and widely practised for over a century. Thus it provides a useful reference point for analyses produced by other faster and more sophisticated techniques, such as the Malvern laser particle size analysis system (Woolfe et al., 2000), and estimates derived from measurements taken with down-hole logging tools (Bücker, pers. com., 1999).

Particle concentration and size distribution in the NGRIP ice core

A novel laser microparticle detector used in conjunction with continuous sample melting has provided a more than 1500 m long record of particle concentration and size distribution of the NGRIP ice core, covering continuously the period approximately from 9.5-100 kyr before present; measurements were at 1.65 m depth resolution, corresponding to approximately 35-200 yr. Particle concentration increased by a factor of 100 in the Last Glacial Maximum (LGM) compared to the Preboreal, and sharp variations of concentration occurred synchronously with rapid changes in the delta18O temperature proxy. The lognormal mode µ of the volume distribution shows clear systematic variations with smaller modes during warmer climates and coarser modes during colder periods. We find µ ~ 1.7 µm diameter during LGM and µ ~ 1.3 µm during the Preboreal. On timescales below several 100 years µ and the particle concentration exhibit a certain degree of independence present especially during warm periods, when µ generally is more variable. Using highly simplifying considerations for atmospheric transport and deposition of particles we infer that (1) the observed changes of µ in the ice largely reflect changes in the size of airborne particles above the ice sheet and (2) changes of µ are indicative of changes in long range atmospheric transport time. From the observed size changes we estimate shorter transit times by roughly 25% during LGM compared to the Preboreal. The associated particle concentration increase from more efficient long range transport is estimated to less than one order of magnitude.