The Function of a Spindle Checkpoint Gene bub-1 in C. elegans Development

BACKGROUND:The serine/threonine kinase BUB1 (Budding Uninhibited by Benzimidazole 1) was originally identified in yeast as a checkpoint protein, based on its mutant's incapacity of delaying the cell cycle in response to loss of microtubules. Our understanding of its function is primarily from studies carried out in yeast S. cerevisiae. It has been shown that it is a component of the mitotic spindle checkpoint and regulates the separation of sister chromatids through its downstream molecules. However, its roles in multi-cellular organisms remain unclear. METHODS AND FINDINGS:In nematode C. elegans, rapid cell divisions primarily occur in embryos and in germline of postembryonic larvae and adults. In addition, a select set of cells undergo a few rounds of cell division postembryonically. One common phenotype associated with impaired cell division is described as Stu (Sterile and Uncoordinated) [1], [2]. We conducted a genetic screen for zygotic mutants that displayed Stu phenotype in C. elegans. We isolated seven Stu mutants that fell into five complementation groups. We report here that two mutations, FanWang5 (fw5) and FanWang8 (fw8) affect the bub-1 gene, a homolog of yeast BUB1. Both mutant alleles of fw5 and fw8 exhibited variable behavioral defects, including developmental arrest, uncoordination and sterility. The number of postembryonically born neurons in the ventral cord decreased and their axon morphology was abnormal. Also, the decrease of neurons in the ventral cord phenotype could not be suppressed by a caspase-3 loss-of-function mutant. In addition, bub-1(fw5 and fw8) mutants showed widespread effects on postembryonic development in many cell lineages. We found that bub-1 functioned maternally in several developmental lineages at the embryonic stage in C. elegans. Studies in yeast have shown that BUB1 functions as a spindle checkpoint protein by regulating the anaphase promoting complex/cyclosome (APC/C). We performed double mutant analysis and observed that bub-1 genetically interacted with several downstream genes, including fzy-1/CDC20, mat-2/APC1 and emb-27/APC6. CONCLUSIONS:Our results demonstrate a conserved role of bub-1 in cell-cycle regulation and reveal that C. elegans bub-1 is required both maternally and zygotically. Further, our genetic analysis is consistent with that the function of bub-1 in C. elegans is likely similar to its yeast and mammalian homologs

Maximum predictive power of the microarray-based models for clinical outcomes is limited by correlation between endpoint and gene expression profile

<p>Abstract</p> <p>Background</p> <p>Microarray data have been used for gene signature selection to predict clinical outcomes. Many studies have attempted to identify factors that affect models' performance with only little success. Fine-tuning of model parameters and optimizing each step of the modeling process often results in over-fitting problems without improving performance.</p> <p>Results</p> <p>We propose a quantitative measurement, termed consistency degree, to detect the correlation between disease endpoint and gene expression profile. Different endpoints were shown to have different consistency degrees to gene expression profiles. The validity of this measurement to estimate the consistency was tested with significance at a p-value less than 2.2e-16 for all of the studied endpoints. According to the consistency degree score, overall survival milestone outcome of multiple myeloma was proposed to extend from 730 days to 1561 days, which is more consistent with gene expression profile.</p> <p>Conclusion</p> <p>For various clinical endpoints, the maximum predictive powers of different microarray-based models are limited by the correlation between endpoint and gene expression profile of disease samples as indicated by the consistency degree score. In addition, previous defined clinical outcomes can also be reassessed and refined more coherent according to related disease gene expression profile. Our findings point to an entirely new direction for assessing the microarray-based predictive models and provide important information to gene signature based clinical applications.</p

Introducing discrete frequency infrared technology for high-throughput biofluid screening

Accurate early diagnosis is critical to patient survival, management and quality of life. Biofluids are key to early diagnosis due to their ease of collection and intimate involvement in human function. Large-scale mid-IR imaging of dried fluid deposits offers a high-throughput molecular analysis paradigm for the biomedical laboratory. The exciting advent of tuneable quantum cascade lasers allows for the collection of discrete frequency infrared data enabling clinically relevant timescales. By scanning targeted frequencies spectral quality, reproducibility and diagnostic potential can be maintained while significantly reducing acquisition time and processing requirements, sampling 16 serum spots with 0.6, 5.1 and 15% relative standard deviation (RSD) for 199, 14 and 9 discrete frequencies respectively. We use this reproducible methodology to show proof of concept rapid diagnostics; 40 unique dried liquid biopsies from brain, breast, lung and skin cancer patients were classified in 2.4 cumulative seconds against 10 non-cancer controls with accuracies of up to 90%

Observation of a topological insulator Dirac cone reshaped by non-magnetic impurity resonance

The massless Dirac electrons found at topological insulator surfaces are thought to be influenced very little by weak, non-magnetic disorder. However, a resonance effect of strongly perturbing non-magnetic impurities has been theoretically predicted to change the dispersion and physical nature of low-energy quasiparticles, resulting in unique particle-like states that lack microscopic translational symmetry. Here we report the direct observation of impurities reshaping the surface Dirac cone of the model three-dimensional topological insulator bismuth selenide. A pronounced kink-like dispersion feature is observed in disorder-enriched samples, and found to be closely associated with the anomaly caused by impurity resonance in the surface state density of states, as observed by dichroic angle-resolved photoemission spectroscopy. The experimental observation of these features, which closely resemble theoretical predictions, has significant implications for the properties of topological Dirac cones in applied scenarios that commonly feature point-defect disorder at surfaces or interfaces. Topological insulators - influence of surface impurities: The electronic properties of topological insulators are robust against perturbations, including the presence of non-magnetic impurities. However, surface impurities can give rise to resonant states near the Dirac point, and if their density becomes sufficiently high it is predicted that they can substantially modify the dispersion of the Dirac cone and develop a collective behaviour that results in the formation of particle-like states that lack microscopic translational symmetry. L. Andrew Wray at Purdue University and at the New York University Shanghai, and colleagues, used angle-resolved photoemission spectroscopy to experimentally observe the reshaping of the surface Dirac cone in a defect-rich sample of the topological insulator Bi2Se3. These results indicate that surface impurities can provide a useful handle to control the properties of topological insulators

Response theory for time-resolved second-harmonic generation and two-photon photoemission

A unified response theory for the time-resolved nonlinear light generation and two-photon photoemission (2PPE) from metal surfaces is presented. The theory allows to describe the dependence of the nonlinear optical response and the photoelectron yield, respectively, on the time dependence of the exciting light field. Quantum-mechanical interference effects affect the results significantly. Contributions to 2PPE due to the optical nonlinearity of the surface region are derived and shown to be relevant close to a plasmon resonance. The interplay between pulse shape, relaxation times of excited electrons, and band structure is analyzed directly in the time domain. While our theory works for arbitrary pulse shapes, we mainly focus on the case of two pulses of the same mean frequency. Difficulties in extracting relaxation rates from pump-probe experiments are discussed, for example due to the effect of detuning of intermediate states on the interference. The theory also allows to determine the range of validity of the optical Bloch equations and of semiclassical rate equations, respectively. Finally, we discuss how collective plasma excitations affect the nonlinear optical response and 2PPE.Comment: 27 pages, including 11 figures, version as publishe

Modeling Chemical Interaction Profiles: II. Molecular Docking, Spectral Data-Activity Relationship, and Structure-Activity Relationship Models for Potent and Weak Inhibitors of Cytochrome P450 CYP3A4 Isozyme

Polypharmacy increasingly has become a topic of public health concern, particularly as the U.S. population ages. Drug labels often contain insufficient information to enable the clinician to safely use multiple drugs. Because many of the drugs are bio-transformed by cytochrome P450 (CYP) enzymes, inhibition of CYP activity has long been associated with potentially adverse health effects. In an attempt to reduce the uncertainty pertaining to CYP-mediated drug-drug/chemical interactions, an interagency collaborative group developed a consensus approach to prioritizing information concerning CYP inhibition. The consensus involved computational molecular docking, spectral data-activity relationship (SDAR), and structure-activity relationship (SAR) models that addressed the clinical potency of CYP inhibition. The models were built upon chemicals that were categorized as either potent or weak inhibitors of the CYP3A4 isozyme. The categorization was carried out using information from clinical trials because currently available in vitro high-throughput screening data were not fully representative of the in vivo potency of inhibition. During categorization it was found that compounds, which break the Lipinski rule of five by molecular weight, were about twice more likely to be inhibitors of CYP3A4 compared to those, which obey the rule. Similarly, among inhibitors that break the rule, potent inhibitors were 2–3 times more frequent. The molecular docking classification relied on logistic regression, by which the docking scores from different docking algorithms, CYP3A4 three-dimensional structures, and binding sites on them were combined in a unified probabilistic model. The SDAR models employed a multiple linear regression approach applied to binned 1D 13C-NMR and 1D 15N-NMR spectral descriptors. Structure-based and physical-chemical descriptors were used as the basis for developing SAR models by the decision forest method. Thirty-three potent inhibitors and 88 weak inhibitors of CYP3A4 were used to train the models. Using these models, a synthetic majority rules consensus classifier was implemented, while the confidence of estimation was assigned following the percent agreement strategy. The classifier was applied to a testing set of 120 inhibitors not included in the development of the models. Five compounds of the test set, including known strong inhibitors dalfopristin and tioconazole, were classified as probable potent inhibitors of CYP3A4. Other known strong inhibitors, such as lopinavir, oltipraz, quercetin, raloxifene, and troglitazone, were among 18 compounds classified as plausible potent inhibitors of CYP3A4. The consensus estimation of inhibition potency is expected to aid in the nomination of pharmaceuticals, dietary supplements, environmental pollutants, and occupational and other chemicals for in-depth evaluation of the CYP3A4 inhibitory activity. It may serve also as an estimate of chemical interactions via CYP3A4 metabolic pharmacokinetic pathways occurring through polypharmacy and nutritional and environmental exposures to chemical mixtures

Collective magnetism at multiferroic vortex domain walls

Topological defects have been playgrounds for many emergent phenomena in complex matter such as superfluids, liquid crystals, and early universe. Recently, vortex-like topological defects with six interlocked structural antiphase and ferroelectric domains merging into a vortex core were revealed in multiferroic hexagonal manganites. Numerous vortices are found to form an intriguing self-organized network. Thus, it is imperative to find out the magnetic nature of these vortices. Using cryogenic magnetic force microscopy, we discovered unprecedented alternating net moments at domain walls around vortices that can correlate over the entire vortex network in hexagonal ErMnO3 The collective nature of domain wall magnetism originates from the uncompensated Er3+ moments and the correlated organization of the vortex network. Furthermore, our proposed model indicates a fascinating phenomenon of field-controllable spin chirality. Our results demonstrate a new route to achieving magnetoelectric coupling at domain walls in single-phase multiferroics, which may be harnessed for nanoscale multifunctional devices.Comment: 18 pages, 10 figure