Graduate Theological Union

Automated annotation of protein function is challenging. As the number of sequenced genomes rapidly grows, the overwhelming majority of protein products can only be annotated computationally. If computational predictions are to be relied upon, it is crucial that the accuracy of these methods be high. Here we report the results from the first large-scale community-based critical assessment of protein function annotation (CAFA) experiment. Fifty-four methods representing the state of the art for protein function prediction were evaluated on a target set of 866 proteins from 11 organisms. Two findings stand out: (i) today's best protein function prediction algorithms substantially outperform widely used first-generation methods, with large gains on all types of targets; and (ii) although the top methods perform well enough to guide experiments, there is considerable need for improvement of currently available tools.

The effect of government programs on the distribution of participants' earnings is important for program evaluation and welfare comparisons.This paper reports es- timates of the effects of JTPA training programs on the distribution of earnings.The estimation uses a new instrumental variable (IV) method that measures program impacts on the quantiles of outcome variables.This quantile treatment effects (QTE) estimator accommodates exogenous covariates and reduces to quantile regres- sion when selection for treatment is exogenously determined.The QTE estimator can be computed as the solution to a convex linear programming problem, although this requires first-step estimation of a nuisance function.We develop distribution theory for the case where the first step is estimated nonparametrically.For women, the empirical results show that the JTPA program had the largest proportional impact at low quantiles.Perhaps surprisingly, however, JTPA training raised the quantiles of earnings for men only in the upper half of the trainee earnings distribution.

Light microscopy provides a simple, cost-effective, and vital method for the diagnosis and screening of hematologic and infectious diseases. In many regions of the world, however, the required equipment is either unavailable or insufficiently portable, and operators may not possess adequate training to make full use of the images obtained. Counterintuitively, these same regions are often well served by mobile phone networks, suggesting the possibility of leveraging portable, camera-enabled mobile phones for diagnostic imaging and telemedicine. Toward this end we have built a mobile phone-mounted light microscope and demonstrated its potential for clinical use by imaging P. falciparum-infected and sickle red blood cells in brightfield and M. tuberculosis-infected sputum samples in fluorescence with LED excitation. In all cases resolution exceeded that necessary to detect blood cell and microorganism morphology, and with the tuberculosis samples we took further advantage of the digitized images to demonstrate automated bacillus counting via image analysis software. We expect such a telemedicine system for global healthcare via mobile phone -- offering inexpensive brightfield and fluorescence microscopy integrated with automated image analysis -- to provide an important tool for disease diagnosis and screening, particularly in the developing world and rural areas where laboratory facilities are scarce but mobile phone infrastructure is extensive.

Functional connectivity (FC) between brain regions is thought to be central to the way in which the brain processes information. Abnormal connectivity is thought to be implicated in a number of diseases. The ability to study FC is therefore a key goal for neuroimaging. Functional connectivity (fc) MRI has become a popular tool to make connectivity measurements but the technique is limited by its indirect nature. A multimodal approach is therefore an attractive means to investigate the electrodynamic mechanisms underlying hemodynamic connectivity. In this paper, we investigate resting state FC using fcMRI and magnetoencephalography (MEG). In fcMRI, we exploit the advantages afforded by ultra high magnetic field. In MEG we apply envelope correlation and coherence techniques to source space projected MEG signals. We show that beamforming provides an excellent means to measure FC in source space using MEG data. However, care must be taken when interpreting these measurements since cross talk between voxels in source space can potentially lead to spurious connectivity and this must be taken into account in all studies of this type. We show good spatial agreement between FC measured independently using MEG and fcMRI; FC between sensorimotor cortices was observed using both modalities, with the best spatial agreement when MEG data are filtered into the β band. This finding helps to reduce the potential confounds associated with each modality alone: while it helps reduce the uncertainties in spatial patterns generated by MEG (brought about by the ill posed inverse problem), addition of electrodynamic metric confirms the neural basis of fcMRI measurements. Finally, we show that multiple MEG based FC metrics allow the potential to move beyond what is possible using fcMRI, and investigate the nature of electrodynamic connectivity. Our results extend those from previous studies and add weight to the argument that neural oscillations are intimately related to functional connectivity and the BOLD response.

Bacterial genes associated with a single trait are often grouped in a contiguous unit of the genome known as a gene cluster. It is difficult to genetically manipulate many gene clusters because of complex, redundant, and integrated host regulation. We have developed a systematic approach to completely specify the genetics of a gene cluster by rebuilding it from the bottom up using only synthetic, well-characterized parts. This process removes all native regulation, including that which is undiscovered. First, all noncoding DNA, regulatory proteins, and nonessential genes are removed. The codons of essential genes are changed to create a DNA sequence as divergent as possible from the wild-type (WT) gene. Recoded genes are computationally scanned to eliminate internal regulation. They are organized into operons and placed under the control of synthetic parts (promoters, ribosome binding sites, and terminators) that are functionally separated by spacer parts. Finally, a controller consisting of genetic sensors and circuits regulates the conditions and dynamics of gene expression. We applied this approach to an agriculturally relevant gene cluster from Klebsiella oxytoca encoding the nitrogen fixation pathway for converting atmospheric N(2) to ammonia. The native gene cluster consists of 20 genes in seven operons and is encoded in 23.5 kb of DNA. We constructed a "refactored" gene cluster that shares little DNA sequence identity with WT and for which the function of every genetic part is defined. This work demonstrates the potential for synthetic biology tools to rewrite the genetics encoding complex biological functions to facilitate access, engineering, and transferability.

The Inner American: A Self-Portrait from 1957 to 1976, by Joseph Veroff, Elizabeth Douvan and Richard A. Kulka and Mental Health in America: Patterns of Help-seeking from 1957 to 1976, by Joseph Veroff, Richard A. Kulka and Elizabeth Douvan Get access Paul Anthony Schwartz Paul Anthony Schwartz Graduate Theological Union Search for other works by this author on: Oxford Academic Google Scholar Sociology of Religion, Volume 43, Issue 2, Summer 1982, Pages 178–180, https://doi.org/10.2307/3710800 Published: 01 July 1982

PURPOSE: A calibrationless parallel imaging reconstruction method, termed simultaneous autocalibrating and k-space estimation (SAKE), is presented. It is a data-driven, coil-by-coil reconstruction method that does not require a separate calibration step for estimating coil sensitivity information. METHODS: In SAKE, an undersampled, multichannel dataset is structured into a single data matrix. The reconstruction is then formulated as a structured low-rank matrix completion problem. An iterative solution that implements a projection-onto-sets algorithm with singular value thresholding is described. RESULTS: Reconstruction results are demonstrated for retrospectively and prospectively undersampled, multichannel Cartesian data having no calibration signals. Additionally, non-Cartesian data reconstruction is presented. Finally, improved image quality is demonstrated by combining SAKE with wavelet-based compressed sensing. CONCLUSION: Because estimation of coil sensitivity information is not needed, the proposed method could potentially benefit MR applications where acquiring accurate calibration data is limiting or not possible at all.

Fluorescence-imaged micropipette aspiration was used to map redistribution of the proteins and lipids in highly extended human red blood cell membranes. Whereas the fluid bilayer distributed uniformly (+/- 10 percent), the underlying, solidlike cytoskeleton of spectrin, actin, and protein 4.1 exhibited a steep gradient in density along the aspirated projection, which was reversible on release from deformation. Quantitation of the cytoskeletal protein density gradients showed that skeletal elasticity is well represented by a grafted polymer network with a ratio of surface dilation modulus to shear modulus of approximately 2:1. Fractionally mobile integral proteins, such as band 3, and highly mobile receptors, such as CD59 as well as glycophorin C in protein 4.1-deficient cells, appeared to be squeezed out of areas dense in the underlying network and enriched in areas of network dilation. This complementary segregation demonstrates patterning of cell surface components by cytoskeletal dilation.

Metabolic engineering for the overproduction of high-value small molecules is dependent upon techniques in directed evolution to improve production titers. The majority of small molecules targeted for overproduction are inconspicuous and cannot be readily obtained by screening. We provide a review on the development of high-throughput colorimetric, fluorescent, and growth-coupled screening techniques, enabling inconspicuous small-molecule detection. We first outline constraints on throughput imposed during the standard directed evolution workflow (library construction, transformation, and screening) and establish a screening and selection ladder on the basis of small-molecule assay throughput and sensitivity. An in-depth analysis of demonstrated screening and selection approaches for small-molecule detection is provided. Particular focus is placed on in vivo biosensor-based detection methods that reduce or eliminate in vitro assay manipulations and increase throughput. We conclude by providing our prospectus for the future, focusing on transcription factor-based detection systems as a natural microbial mode of small-molecule detection.

Systems biology seeks to develop a complete understanding of cellular mechanisms by studying the functions of intra- and inter-cellular molecular interactions that trigger and coordinate cellular events. However, the complexity of biological systems causes accurate and precise systems biology experimentation to be a difficult task. Most biological experimentation focuses on highly detailed investigation of a single signaling mechanism, which lacks the throughput necessary to reconstruct the entirety of the biological system, while high-throughput testing often lacks the fidelity and detail necessary to fully comprehend the mechanisms of signal propagation. Systems biology experimentation, however, can benefit greatly from the progress in the development of microfluidic devices. Microfluidics provides the opportunity to study cells effectively on both a single- and multi-cellular level with high-resolution and localized application of experimental conditions with biomimetic physiological conditions. Additionally, the ability to massively array devices on a chip opens the door for high-throughput, high fidelity experimentation to aid in accurate and precise unraveling of the intertwined signaling systems that compose the inner workings of the cell.

A fully integrated genomic analysis microsystem including microfabricated heaters, temperature sensors, and PCR chambers directly connected to capillary electrophoretic separation channels has been constructed. Valves and hydrophobic vents provide controlled and sensorless sample positioning and immobilization into 200 nL PCR chambers. The use of microfabricated heating and temperature sensing elements improves the heating and cooling rates for the PCR reaction to 20 degree C s(-1). The amplified PCR product, labeled on-column with an intercalating fluorescent dye, is injected into the gel-filled capillary for electrophoretic analysis. Successful sex determination using a multiplex PCR reaction from human genomic DNA is demonstrated in less than 15 min. This device is an important step toward a microfabricated genomic microprocessor for use in forensics and point-of-care molecular medical diagnostics.

The use of an effective intermolecular potential often involves a compromise between more accurate, complex functional forms and more tractable simple representations. To study this choice in detail, we systematically derive coarse-grained isotropic pair potentials that accurately reproduce the oxygen-oxygen radial distribution function of the TIP4P-Ew water model at state points over density ranges from 0.88 to 1.30 g/cm3 and temperature ranges from 235 to 310 K. Although by construction these effective potentials correctly represent the isothermal compressibility of TIP4P-Ew water, they do not accurately resolve other thermodynamic properties such as the virial pressure, the internal energy, or thermodynamic anomalies. Because at a given state point the pair potential that reproduces the pair structure is unique, we have therefore explicitly demonstrated that it is impossible to simultaneously represent the pair structure and several key equilibrium thermodynamic properties of water with state-point dependent radially symmetric pair potentials. We argue that such representability problems are related to, but different from, more widely acknowledged transferability problems and discuss in detail the implications this has for the modeling of water and other liquids by coarse-grained potentials. Nevertheless, regardless of thermodynamic inconsistencies, the state-point dependent effective potentials for water do generate structural and dynamical anomalies.

Deformability of blood cells is known to influence vascular flow and contribute to vascular complications. Medications for hematologic diseases have the potential to modulate these complications if they alter blood cell deformability. Here we report the effect of chemotherapy on leukemia cell mechanical properties. Acute lymphoblastic and acute myeloid leukemia cells were incubated with standard induction chemotherapy, and individual cell stiffness was tracked with atomic force microscopy. When exposed to dexamethasone or daunorubicin, leukemia cell stiffness increased by nearly 2 orders of magnitude, which decreased their passage through microfluidic channels. This stiffness increase occurred before caspase activation and peaked after completion of cell death, and the rate of stiffness increase depended on chemotherapy type. Stiffening with cell death occurred for all cell types investigated and may be due to dynamic changes in the actin cytoskeleton. These observations suggest that chemotherapy itself may increase the risk of vascular complications in acute leukemia.

Flies rely heavily on visual feedback for several aspects of flight control. As a fly approaches an object, the image projected across its retina expands, providing the fly with visual feedback that can be used either to trigger a collision-avoidance maneuver or a landing response. To determine how a fly makes the decision to land on or avoid a looming object, we measured the behaviors generated in response to an expanding image during tethered flight in a visual closed-loop flight arena. During these experiments, each fly varied its wing-stroke kinematics to actively control the azimuth position of a 15 degrees x 15 degrees square within its visual field. Periodically, the square symmetrically expanded in both the horizontal and vertical directions. We measured changes in the fly's wing-stroke amplitude and frequency in response to the expanding square while optically tracking the position of its legs to monitor stereotyped landing responses. Although this stimulus could elicit both the landing responses and collision-avoidance reactions, separate pathways appear to mediate the two behaviors. For example, if the square is in the lateral portion of the fly's field of view at the onset of expansion, the fly increases stroke amplitude in one wing while decreasing amplitude in the other, indicative of a collision-avoidance maneuver. In contrast, frontal expansion elicits an increase in wing-beat frequency and leg extension, indicative of a landing response. To further characterize the sensitivity of these responses to expansion rate, we tested a range of expansion velocities from 100 to 10 000 degrees s(-1). Differences in the latency of both the collision-avoidance reactions and the landing responses with expansion rate supported the hypothesis that the two behaviors are mediated by separate pathways. To examine the effects of visual feedback on the magnitude and time course of the two behaviors, we presented the stimulus under open-loop conditions, such that the fly's response did not alter the position of the expanding square. From our results we suggest a model that takes into account the spatial sensitivities and temporal latencies of the collision-avoidance and landing responses, and is sufficient to schematically represent how the fly uses integration of motion information in deciding whether to turn or land when confronted with an expanding object.

The goal of this study was to characterize longitudinal changes in bone microarchitecture and function in women treated with an established antifracture therapeutic. In this double-blind, placebo-controlled pilot study, 53 early postmenopausal women with low bone density (age = 56 ± 4 years; femoral neck T-score = -1.5 ± 0.6) were monitored by high-resolution peripheral quantitative computed tomography (HR-pQCT) for 24 months following randomization to alendronate (ALN) or placebo (PBO) treatment groups. Subjects underwent annual HR-pQCT imaging of the distal radius and tibia, dual-energy X-ray absorptiometry (DXA), and determination of biochemical markers of bone turnover (BSAP and uNTx). In addition to bone density and microarchitecture assessment, regional analysis, cortical porosity quantification, and micro-finite-element analysis were performed. After 24 months of treatment, at the distal tibia but not the radius, HR-pQCT measures showed significant improvements over baseline in the ALN group, particularly densitometric measures in the cortical and trabecular compartments and endocortical geometry (cortical thickness and area, medullary area) (p < .05). Cortical volumetric bone mineral density (vBMD) in the tibia alone showed a significant difference between treatment groups after 24 months (p < .05); however, regionally, significant differences in Tb.vBMD, Tb.N, and Ct.Th were found for the lateral quadrant of the radius (p < .05). Spearman correlation analysis revealed that the biomechanical response to ALN in the radius and tibia was specifically associated with changes in trabecular microarchitecture (|ρ| = 0.51 to 0.80, p < .05), whereas PBO progression of bone loss was associated with a broad range of changes in density, geometry, and microarchitecture (|ρ| = 0.56 to 0.89, p < .05). Baseline cortical geometry and porosity measures best predicted ALN-induced change in biomechanics at both sites (ρ > 0.48, p < .05). These findings suggest a more pronounced response to ALN in the tibia than in the radius, driven by trabecular and endocortical changes.

Thrombus formation in intracranial aneurysms, while sometimes stabilizing lesion growth, can present additional risk of thrombo-embolism. The role of hemodynamics in the progression of aneurysmal disease can be elucidated by patient-specific computational modeling. In our previous work, patient-specific computational fluid dynamics (CFD) models were constructed from MRI data for three patients who had fusiform basilar aneurysms that were thrombus-free and then proceeded to develop intraluminal thrombus. In this study, we investigated the effect of increased flow residence time (RT) by modeling passive scalar advection in the same aneurysmal geometries. Non-Newtonian pulsatile flow simulations were carried out in base-line geometries and a new postprocessing technique, referred to as "virtual ink" and based on the passive scalar distribution maps, was used to visualize the flow and estimate the flow RT. The virtual ink technique clearly depicted regions of flow separation. The flow RT at different locations adjacent to aneurysmal walls was calculated as the time the virtual ink scalar remained above a threshold value. The RT values obtained in different areas were then correlated with the location of intra-aneurysmal thrombus observed at a follow-up MR study. For each patient, the wall shear stress (WSS) distribution was also obtained from CFD simulations and correlated with thrombus location. The correlation analysis determined a significant relationship between regions where CFD predicted either an increased RT or low WSS and the regions where thrombus deposition was observed to occur in vivo. A model including both low WSS and increased RT predicted thrombus-prone regions significantly better than the models with RT or WSS alone.

Continued advances in metabolic engineering are increasing the number of small molecules being targeted for microbial production. Pathway yields and productivities, however, are often suboptimal, and strain improvement remains a persistent challenge given that the majority of small molecules are difficult to screen for and their biosynthesis does not improve host fitness. In this work, we have developed a generalized approach to screen or select for improved small-molecule biosynthesis using transcription factor-based biosensors. Using a tetracycline resistance gene 3' of a small-molecule inducible promoter, host antibiotic resistance, and hence growth rate, was coupled to either small-molecule concentration in the growth medium or a small-molecule production phenotype. Biosensors were constructed for two important chemical classes, dicarboxylic acids and alcohols, using transcription factor-promoter pairs derived from Pseudomonas putida, Thauera butanivorans, or E. coli. Transcription factors were selected for specific activation by either succinate, adipate, or 1-butanol, and we demonstrate product-dependent growth in E. coli using all three compounds. The 1-butanol biosensor was applied in a proof-of-principle liquid culture screen to optimize 1-butanol biosynthesis in engineered E. coli, identifying a pathway variant yielding a 35% increase in 1-butanol specific productivity through optimization of enzyme expression levels. Lastly, to demonstrate the capacity to select for enzymatic activity, the 1-butanol biosensor was applied as synthetic selection, coupling in vivo 1-butanol biosynthesis to E. coli fitness, and an 120-fold enrichment for a 1-butanol production phenotype was observed following a single round of positive selection.

Tagged MRI and finite-element (FE) analysis are valuable tools in analyzing cardiac mechanics. To determine systolic material parameters in three-dimensional stress-strain relationships, we used tagged MRI to validate FE models of left ventricular (LV) aneurysm. Five sheep underwent anteroapical myocardial infarction (25% of LV mass) and 22 wk later underwent tagged MRI. Asymmetric FE models of the LV were formed to in vivo geometry from MRI and included aneurysm material properties measured with biaxial stretching, LV pressure measurements, and myofiber helix angles measured with diffusion tensor MRI. Systolic material parameters were determined that enabled FE models to reproduce midwall, systolic myocardial strains from tagged MRI (630 +/- 187 strain comparisons/animal). When contractile stress equal to 40% of the myofiber stress was added transverse to the muscle fiber, myocardial strain agreement improved by 27% between FE model predictions and experimental measurements (RMS error decreased from 0.074 +/- 0.016 to 0.054 +/- 0.011, P < 0.05). In infarct border zone (BZ), end-systolic midwall stress was elevated in both fiber (24.2 +/- 2.7 to 29.9 +/- 2.4 kPa, P < 0.01) and cross-fiber (5.5 +/- 0.7 to 11.7 +/- 1.3 kPa, P = 0.02) directions relative to noninfarct regions. Contrary to previous hypotheses but consistent with biaxial stretching experiments, active cross-fiber stress development is an integral part of LV systole; FE analysis with only uniaxial contracting stress is insufficient. Stress calculations from these validated models show 24% increase in fiber stress and 115% increase in cross-fiber stress at the BZ relative to remote regions, which may contribute to LV remodeling.

The reviewed literature reported on plagiarism in the context of the digital era from the perspective of a broader educational spectrum. The authors of this review ask questions with regard to what constitutes plagiarism, how prevalent plagiarism is in our schools, colleges, and society, what is done to prevent and reduce plagiarism, the attitudes of faculty toward academic dishonesty in general, and individual differences as predictors of academic dishonesty. This article identifies research questions that have not been addressed sufficiently in the literature and suggests specific research areas for further investigation.

PURPOSE: To demonstrate a noninvasive method to visualize and analyze the parafoveal capillary network in humans. METHODS: An adaptive optics scanning laser ophthalmoscope was used to acquire high resolution retinal videos on human subjects. Video processing tools that enhance motion contrast were developed and applied to the videos to generate montages of parafoveal retinal capillaries. The capillary network and foveal avascular zone (FAZ) were extracted using video and image analysis algorithms. The capillary densities in the zone immediately outside the FAZ were calculated and the variation in density as a function of direction was investigated. Extracted FAZ geometries were used to calculate area and effective diameters. The authors also compared their method against fluorescein angiography (FA) for one subject. RESULTS: The parafoveal capillaries were clearly visible when the motion contrast in noninvasive videos was enhanced. There was a marked improvement in the contrast of the parafoveal capillaries when compared to the unprocessed videos. The average FAZ area was 0.323 mm(2), with an average effective diameter of 633 microm. There was no variation in capillary density near the FAZ in different directions. CONCLUSIONS: Using motion cues to enhance vessel contrast is a powerful tool for visualizing the capillary network, in the absence of contrast agents. The authors demonstrate a tool to study the microcirculation of healthy subjects noninvasively.