Publications

The advancement of the computational biology field hinges on progress in three fundamental directions—the development of new computational algorithms, the availability of informatics resource management infrastructures and the capability of tools to interoperate and synergize. There is an explosion in algorithms and tools for computational biology, which makes it difficult for biologists to find, compare and integrate such resources. We describe a new infrastructure, iTools, for managing the query, traversal and comparison of diverse computational biology resources. Specifically, iTools stores information about three types of resources—data, software tools and web-services. The iTools design, implementation and resource meta-data content reflect the broad research, computational, applied and scientific expertise available at the seven National Centers for Biomedical Computing. iTools provides a system for classification, categorization and integration of different computational biology resources across space-and-time scales, biomedical problems, computational infrastructures and mathematical foundations. A large number of resources are already iTools-accessible to the community and this infrastructure is rapidly growing. iTools includes human and machine interfaces to its resource meta-data repository. Investigators or computer programs may utilize these interfaces to search, compare, expand, revise and mine meta-data descriptions of existent computational biology resources. We propose two ways to browse and display the iTools dynamic collection of resources. The first one is based on an ontology of computational biology resources, and the second one is derived from hyperbolic projections of manifolds or complex structures onto planar discs. iTools is an open source project both in terms of the source code development as well as its meta-data content. iTools employs a decentralized, portable, scalable and lightweight framework for long-term resource management. We demonstrate several applications of iTools as a framework for integrated bioinformatics. iTools and the complete details about its specifications, usage and interfaces are available at the iTools web page http://iTools.ccb.ucla.edu.

Whereas high angular resolution reconstruction methods for diffusion MRI can estimate multiple dominant fibre orientations within a single imaging voxel, they are fundamentally limited in certain cases of complex subvoxel fibre structures, resulting in ambiguous local orientation distribution functions. In this article we address the important problem of disambiguating such complex subvoxel fibre tract configurations, with the purpose of improving the performance of fibre tractography. We do so by extending a curve inference method to distinguish between the cases of curving and fanning fibre bundles using differential geometric estimates in a local neighbourhood. The key benefit of this method is the inference of curves, instead of only fibre orientations, to model the underlying fibre bundles. This in turn allows distinct fibre geometries that contain nearly identical sets of fibre orientations at a voxel, to be distinguished from one another. Experimental results demonstrate the ability of the method to successfully label voxels into one of the above categories and improve the performance of a fibre-tracking algorithm.

OBJECTIVE: To evaluate volumes and asymmetry of superior temporal gyrus (STG) and correlate these measures with a neurocognitive evaluation of verbal performance in Williams syndrome (WS) and in a typically developing age-matched and sex-matched group. BACKGROUND: Despite initial claims of language strength in WS, recent studies suggest delayed language milestones. The STG is implicated in linguistic processing and is a highly lateralized brain region. METHOD: Here, we examined STG volumes and asymmetry of STG in WS patients and in age-matched controls. We also correlated volume of STG with a subset of verbal measures. Magnetic resonance imaging scans were obtained on a GE 1.5-T magnet with 1.5-mm contiguous slices, and were used to measure whole gray matter, white matter, and cerebrospinal fluid volumes, and also STG volume. RESULTS: Results revealed significantly reduced intracranial volume in WS patients, compared with controls. Right and left STG were also significantly smaller in WS patients. In addition, compared with normal controls, a lack of normal left >right STG asymmetry was evident in WS. Also of note was the finding that, in contrast to controls, WS patients did not reveal a positive correlation between verbal intelligence quotient and left STG volume, which further suggests a disruption in this region of the brain. CONCLUSIONS: In conclusion, atypical patterns of asymmetry and reduced STG volume in WS were observed, which may, in part, contribute to some of the linguistic impairments found in this cohort of WS patients.

A lyotropic nonionic lamellar system composed of pentaethyleneglycol mono n-dodecyl ether and D(2)O was studied using natural abundance (13)C NMR under magic-angle spinning. Applying a two-dimensional recoupling method proposed by Dvinskikh (R-PDLF), (1)H-(13)C dipolar couplings were estimated over a range of temperatures (300-335 K), thus enabling analysis of structural changes in the liquid crystalline system. The results obtained are used to correlate the conformation and mobility of local sites in the surfactant molecule with overall changes in the lamellar structure.

BACKGROUND: In chronic schizophrenia and chronic bipolar disorder, gamma band (30-100 Hz) auditory steady-state electroencephalogram responses (ASSRs) are reduced in power and phase locking, likely reflecting neural circuit dysfunction. Here we examined whether gamma ASSR deficits are also present at first hospitalization for psychosis. METHODS: Subjects were 16 first episode schizophrenia patients (SZ), 16 first episode affective disorder patients (AFF) (13 with bipolar disorder), and 33 healthy control subjects (HC). Stimuli were 20-, 30-, and 40-Hz binaural click trains. The ASSR phase locking and evoked power were analyzed with the Morlet wavelet transform. RESULTS: At 40-Hz stimulation, SZ and AFF had significantly reduced phase locking compared with HC. This deficit was more pronounced over the left hemisphere in SZ. Evoked power at 40 Hz was also reduced in the patients compared with HC. At 30-Hz stimulation phase locking and evoked power were reduced in both patient groups. The 20-Hz ASSR did not differ between groups, but phase locking and evoked power of the 40-Hz harmonic of the 20-Hz ASSR were reduced in both SZ and AFF. Phase locking of this 40-Hz harmonic was correlated with total positive symptoms in SZ. CONCLUSIONS: The gamma ASSR deficit is present at first hospitalization for both schizophrenia and affective disorder but shows a left hemisphere bias in first hospitalized SZ. Some of the neural circuitry abnormalities underlying the gamma ASSR deficit might be common to psychoses in general, whereas others might be specific to particular disorders.

Using bicontinuous microemulsions as templates opens a new field for the design of novel structures and thus novel materials, but has significant challenges due to the very small composition and temperature windows in which microemulsions are bicontinuous. In previous work we had shown that we can take a ternary base system (water-n-dodecane—C 13/15E 5), add monomer and cross-linker ( N-isopropylacrylamide and N, N’-methylenebisacrylamide) to the water phase, and add a gelator (12-hydroxyoctadecanoic acid) to the oil phase while remaining in the one-phase region of the phase diagram. It was also possible to allow the gelator to form an organogel by changing the temperature such that we crossed the sol—gel line, which fell within the one-phase region. In this work, we show conclusively that addition of the monomers and the gelator does not affect the microemulsion microstructure and that, even in the gelled state, the polymerizable microemulsion is indeed bicontinuous. 1H NMR self-diffusion, conductivity, and small-angle neutron scattering measurements all confirm the bicontinuous nature of the gelled polymerizable microemulsion.

Proton-detected NMR diffusion and (31)P NMR chemical shifts/bandwidths measurements were used to investigate a series of liposomal formulations where size and PEGylation extent need to be controlled for ultrasound mediated drug release. The width of the (31)P line is sensitive to aggregate size and shape and self-diffusion (1)H NMR conveys information about diffusional motion, size, and PEGylation extent. Measurements were performed on the formulations at their original pH, osmolality, and lipid concentration. These contained variable amounts of PEGylated phospholipid (herein referred to as PEG-lipid) and cholesterol. At high levels of PEG-lipid (11.5 and 15 mol%) the self-diffusion (1)H NMR revealed the coexistence of two entities with distinct diffusion coefficients: micelles (1.3 to 3x10(-11) m(2)/s) and liposomes (approximately 5x10(-12) m(2)/s). The (31)P spectra showed a broad liposome signal and two distinct narrow lines that were unaffected by temperature. The narrow lines arise from mixed micelles comprising both PEG-lipids and phospholipids. The echo decay in the diffusion experiments could be described as a sum of exponentials revealing that the exchange of PEG-lipid between liposomes and micellar aggregates is slower than the experimental observation time. For low amounts of PEG-lipid (1 and 4.5 mol%) the (31)P spectra consisted of a broad signal typically obtained for liposomes and the diffusion data were best described by a single exponential decay attributed solely to liposomes. For intermediate amounts of PEG-lipid (8 mol%), micellization started to occur and the diffusion data could no longer be fitted to a single or bi-exponential decay. Instead, the data were best described by a log-normal distribution of diffusion coefficients. The most efficient PEG-lipid incorporation in liposomes (about 8 mol%) was achieved for lower molecular weight PEG (2000 Da vs 5000 Da) and when the PEG-lipid acyl chain length matched the acyl chain length of the liposomal core phospholipid. Simultaneously to the PEGylation extent, self-diffusion (1)H NMR provides information about the size of micelles and liposomes. The size of the micellar aggregates decreased as the PEG-lipid content was increased while the liposome size remained invariant.

Cartilage sections were cut from the middle zone of pig knee articular cartilage and attached to substrates in two different kinds of newly designed ’pressure cells’, one for fluorescence the other for NMR measurements. The fluorescence cell was filled with buffer solution containing fluorescently marked 70 kDa dextran which was allowed to diffuse into the cartilage pores. A second glass surface was then pressed down onto the thin cartilage sample under different loads (pressures), and the resulting compression (strain) and change in pore volume were measured as a function of time, simultaneously with measurements of the lateral diffusion and flow pattern of the dextran molecules using Fluorescence Recovery After Photobleaching (FRAP). Complementary experiments were made on the normal diffusion coefficients of pure electrolyte solutions (no dextran) in thicker cartilage sections with pulse-gradient NMR using a new pressure cell suitable for such measurements. Taken together our results show that the highly anisotropic structure of cartilage has a strong effect on the way fluid diffuses laterally and normally at different stages of compression. Our results also show how geometric constraints on a cartilage network and trapped high MW polymer such as HA during normal compressions are likely to affect both the normal and the lateral mobilities of polyelectrolytes and water.

The electrical activity in the electroencephalogram (EEG) and the event-related potentials extracted from the EEG provide the greatest temporal resolution for examining brain function. When coupled with the high spatial resolution of structural magnetic resonance imaging (sMRI), the combined techniques provide a powerful tool for neuroscience in the examination of brain abnormalities in major psychiatric illnesses. Over the last 20 years, our work has examined brain structure and function in schizophrenia. Both EEG and MRI measures have indicated profound abnormalities in schizophrenia within the temporal lobe, particularly marked over the left hemisphere. Our studies of patients first hospitalized due to psychosis revealed the early course of the disease to be characterized by progressive impairment and cortical gray matter reduction, most intense near the time of first hospitalization. Knowledge of those locations and brain signals affected early should help understand the basic physiological defect underlying this progression, with potential implications for new therapeutic interventions.

CONTEXT: Previous magnetic resonance imaging (MRI) findings have demonstrated psychopathological symptom-related smaller gray matter volumes in various cingulate gyrus subregions in schizophrenia and bipolar disorder. However, it is unclear whether these gray matter abnormalities show a subregional specificity to either disorder and whether they show postonset progression. OBJECTIVE: To determine whether there are initial and progressive gray matter volume deficits in cingulate gyrus subregions in patients with first-episode schizophrenia (FESZ) and patients with first-episode affective psychosis (FEAFF, mainly manic) and their specificity to FESZ or FEAFF. DESIGN: A naturalistic cross-sectional study at first hospitalization for psychosis and a longitudinal follow-up approximately 1(1/2) years later. SETTING AND PARTICIPANTS: Patients were from a private psychiatric hospital. Thirty-nine patients with FESZ and 41 with FEAFF at first hospitalization for psychosis and 40 healthy control subjects (HCs) recruited from the community underwent high-spatial-resolution MRI, with follow-up scans in 17 FESZ patients, 18 FEAFF patients, and 18 HCs. Individual subjects were matched for age, sex, parental socioeconomic status, and handedness. MAIN OUTCOME MEASURES: Cingulate gyrus gray matter volumes in 3 anterior subregions (subgenual, affective, and cognitive) and 1 posterior subregion, and whether there was a paracingulate sulcus.