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1.  Nonparametric Bayes Modeling for Case Control Studies with Many Predictors 
Biometrics  2015;72(1):184-192.
Summary
It is common in biomedical research to run case-control studies involving high-dimensional predictors, with the main goal being detection of the sparse subset of predictors having a significant association with disease. Usual analyses rely on independent screening, considering each predictor one at a time, or in some cases on logistic regression assuming no interactions. We propose a fundamentally different approach based on a nonparametric Bayesian low rank tensor factorization model for the retrospective likelihood. Our model allows a very flexible structure in characterizing the distribution of multivariate variables as unknown and without any linear assumptions as in logistic regression. Predictors are excluded only if they have no impact on disease risk, either directly or through interactions with other predictors. Hence, we obtain an omnibus approach for screening for important predictors. Computation relies on an efficient Gibbs sampler. The methods are shown to have high power and low false discovery rates in simulation studies, and we consider an application to an epidemiology study of birth defects.
doi:10.1111/biom.12411
PMCID: PMC4803642  PMID: 26394204
Bayesian nonparametrics; Big data; Epidemiology; Retrospective likelihood; Sparse parallel factor analysis model; Tensor factorization
2.  Polyhydramnios in Lrp4 knockout mice with bilateral kidney agenesis: Defects in the pathways of amniotic fluid clearance 
Scientific Reports  2016;6:20241.
Amniotic fluid volume during mid-to-late gestation depends mainly on the urine excretion from the foetal kidneys and partly on the fluid secretion from the foetal lungs during foetal breathing-like movements. Urine is necessary for foetal breathing-like movements, which is critical for foetal lung development. Bilateral renal agenesis and/or obstruction of the urinary tract lead to oligohydramnios, which causes infant death within a short period after birth due to pulmonary hypoplasia. Lrp4, which functions as an agrin receptor, is essential for the formation of neuromuscular junctions. Herein, we report novel phenotypes of Lrp4 knockout (Lrp4−/−) mice. Most Lrp4−/− foetuses showed unilateral or bilateral kidney agenesis, and Lrp4 knockout resulted in polyhydramnios. The loss of Lrp4 compromised foetal swallowing and breathing-like movements and downregulated the expression of aquaporin-9 in the foetal membrane and aquaporin-1 in the placenta, which possibly affected the amniotic fluid clearance. These results suggest that amniotic fluid removal was compromised in Lrp4−/− foetuses, resulting in polyhydramnios despite the impairment of urine production. Our findings indicate that amniotic fluid removal plays an essential role in regulating the amniotic fluid volume.
doi:10.1038/srep20241
PMCID: PMC4742865  PMID: 26847765
3.  Use of metabolomics for the chemotaxonomy of legume-associated Ascochyta and allied genera 
Scientific Reports  2016;6:20192.
Chemotaxonomy and the comparative analysis of metabolic features of fungi have the potential to provide valuable information relating to ecology and evolution, but have not been fully explored in fungal biology. Here, we investigated the chemical diversity of legume-associated Ascochyta and Phoma species and the possible use of a metabolomics approach using liquid chromatography-mass spectrometry for their classification. The metabolic features of 45 strains including 11 known species isolated from various legumes were extracted, and the datasets were analyzed using chemometrics methods such as principal component and hierarchical clustering analyses. We found a high degree of intra-species consistency in metabolic profiles, but inter-species diversity was high. Molecular phylogenies of the legume-associated Ascochyta/Phoma species were estimated using sequence data from three protein-coding genes and the five major chemical groups that were detected in the hierarchical clustering analysis were mapped to the phylogeny. Clusters based on similarity of metabolic features were largely congruent with the species phylogeny. These results indicated that evolutionarily distinct fungal lineages have diversified their metabolic capacities as they have evolved independently. This whole metabolomics approach may be an effective tool for chemotaxonomy of fungal taxa lacking information on their metabolic content.
doi:10.1038/srep20192
PMCID: PMC4742866  PMID: 26847260
4.  New Flexible Channels for Room Temperature Tunneling Field Effect Transistors 
Scientific Reports  2016;6:20293.
Tunneling field effect transistors (TFETs) have been proposed to overcome the fundamental issues of Si based transistors, such as short channel effect, finite leakage current, and high contact resistance. Unfortunately, most if not all TFETs are operational only at cryogenic temperatures. Here we report that iron (Fe) quantum dots functionalized boron nitride nanotubes (QDs-BNNTs) can be used as the flexible tunneling channels of TFETs at room temperatures. The electrical insulating BNNTs are used as the one-dimensional (1D) substrates to confine the uniform formation of Fe QDs on their surface as the flexible tunneling channel. Consistent semiconductor-like transport behaviors under various bending conditions are detected by scanning tunneling spectroscopy in a transmission electron microscopy system (in-situ STM-TEM). As suggested by computer simulation, the uniform distribution of Fe QDs enable an averaging effect on the possible electron tunneling pathways, which is responsible for the consistent transport properties that are not sensitive to bending.
doi:10.1038/srep20293
PMCID: PMC4742867  PMID: 26846587
5.  Skyrmion motion driven by oscillating magnetic field 
Scientific Reports  2016;6:20360.
The one-dimensional magnetic skyrmion motion induced by an electric current has attracted much interest because of its application potential in next-generation magnetic memory devices. Recently, the unidirectional motion of large (20 μm in diameter) magnetic bubbles with two-dimensional skyrmion topology, driven by an oscillating magnetic field, has also been demonstrated. For application in high-density memory devices, it is preferable to reduce the size of skyrmion. Here we show by numerical simulation that a skyrmion of a few tens of nanometres can also be driven by high-frequency field oscillations, but with a different direction of motion from the in-plane component of the tilted oscillating field. We found that a high-frequency field for small skyrmions can excite skyrmion resonant modes and that a combination of different modes results in a final skyrmion motion with a helical trajectory. Because this helical motion depends on the frequency of the field, we can control both the speed and the direction of the skyrmion motion, which is a distinguishable characteristic compared with other methods.
doi:10.1038/srep20360
PMCID: PMC4742868  PMID: 26847334
6.  Nanoquinacrine induced apoptosis in cervical cancer stem cells through the inhibition of hedgehog-GLI1 cascade: Role of GLI-1 
Scientific Reports  2016;6:20600.
To improve the pharmacokinetics and to study the anti-cervical cancer and anti-stem cells (CSCs) mechanism of Quinacrine (QC), a spherical nano particle of QC (i.e. NQC) was prepared and characterized. QC and NQC showed higher cytotoxicity in multiple cancer cells than the normal epithelial cells. NQC exhibited more toxicity in cervical cancer cells and its CSCs than QC. A dose-dependent decreased expression of Hedgehog-GLI (HH-GLI) components were noted in NQC treated HeLa cells and its CSCs. NQC increased the expressions of negatively regulated HH-GLI components (GSK3β, PTEN) and caused apoptosis in CSCs. Reduction of GLI1 at mRNA and promoter level were noted after NQC exposure. The expressions of HH-GLI components, GLI1 promoter activity and apoptosis were unaltered in NQC treated GLI1-knockdown cells. In silico, cell based and in vitro reconstitution assay revealed that NQC inhibit HH-GLI cascade by binding to the consensus sequence (5′GACCACCCA3′) of GLI1 in GLI-DNA complex through destabilizing DNA-GLI1 complex. NQC reduced the tumors size and proliferation marker Ki-67 in an in vivo xenograft mice model. Thus, NQC induced apoptosis in cancers through inhibition of HH-GLI cascade by GLI1. Detail interaction of QC-DNA-GLI complex can pave path for anticancer drug design.
doi:10.1038/srep20600
PMCID: PMC4742869  PMID: 26846872
7.  Microbiologically Influenced Corrosion of 2707 Hyper-Duplex Stainless Steel by Marine Pseudomonas aeruginosa Biofilm 
Scientific Reports  2016;6:20190.
Microbiologically Influenced Corrosion (MIC) is a serious problem in many industries because it causes huge economic losses. Due to its excellent resistance to chemical corrosion, 2707 hyper duplex stainless steel (2707 HDSS) has been used in the marine environment. However, its resistance to MIC was not experimentally proven. In this study, the MIC behavior of 2707 HDSS caused by the marine aerobe Pseudomonas aeruginosa was investigated. Electrochemical analyses demonstrated a positive shift in the corrosion potential and an increase in the corrosion current density in the presence of the P. aeruginosa biofilm in the 2216E medium. X-ray photoelectron spectroscopy (XPS) analysis results showed a decrease in Cr content on the coupon surface beneath the biofilm. The pit imaging analysis showed that the P. aeruginosa biofilm caused a largest pit depth of 0.69 μm in 14 days of incubation. Although this was quite small, it indicated that 2707 HDSS was not completely immune to MIC by the P. aeruginosa biofilm.
doi:10.1038/srep20190
PMCID: PMC4742871  PMID: 26846970
8.  Dirac fermions at high-index surfaces of bismuth chalcogenide topological insulator nanostructures 
Scientific Reports  2016;6:20220.
Binary bismuth chalcogenides Bi2Se3, Bi2Te3, and related materials are currently being extensively investigated as the reference topological insulators (TIs) due to their simple surface-state band dispersion (single Dirac cone) and relatively large bulk band gaps. Nanostructures of TIs are of particular interest as an increased surface-to-volume ratio enhances the contribution of surfaces states, meaning they are promising candidates for potential device applications. So far, the vast majority of research efforts have focused on the low-energy (0001) surfaces, which correspond to natural cleavage planes in these layered materials. However, the surfaces of low-dimensional nanostructures (nanoplatelets, nanowires, nanoribbons) inevitably involve higher-index facets. We perform a systematic ab initio investigation of the surfaces of bismuth chalcogenide TI nanostructures characterized by different crystallographic orientations, atomic structures and stoichiometric compositions. We find several stable terminations of high-index surfaces, which can be realized at different values of the chemical potential of one of the constituent elements. For the uniquely defined stoichiometric termination, the topological Dirac fermion states are shown to be strongly anisotropic with a clear dependence of Fermi velocities and spin polarization on the surface orientation. Self-doping effects and the presence of topologically trivial mid-gap states are found to characterize the non-stoichiometric surfaces. The results of our study pave the way towards experimental control of topologically protected surface states in bismuth chalcogenide nanostructures.
doi:10.1038/srep20220
PMCID: PMC4742872  PMID: 26847409
9.  Breast Cancer MDA-MB-231 Cells Use Secreted Heat Shock Protein-90alpha (Hsp90α) to Survive a Hostile Hypoxic Environment 
Scientific Reports  2016;6:20605.
Rapidly growing tumours in vivo often outgrow their surrounding available blood supply, subjecting themselves to a severely hypoxic microenvironment. Understanding how tumour cells adapt themselves to survive hypoxia may help to develop new treatments of the tumours. Given the limited blood perfusion to the enlarging tumour, whatever factor(s) that allows the tumour cells to survive likely comes from the tumour cells themselves or its associated stromal cells. In this report, we show that HIF-1α-overexpressing breast cancer cells, MDA-MB-231, secrete heat shock protein-90alpha (Hsp90α) and use it to survive under hypoxia. Depletion of Hsp90α secretion from the tumour cells was permissive to cytotoxicity by hypoxia, whereas supplementation of Hsp90α-knockout tumour cells with recombinant Hsp90α, but not Hsp90β, protein prevented hypoxia-induced cell death via an autocrine mechanism through the LDL receptor-related protein-1 (LRP1) receptor. Finally, direct inhibition of the secreted Hsp90α with monoclonal antibody, 1G6-D7, enhanced tumour cell death under hypoxia. Therefore, secreted Hsp90α is a novel survival factor for certain tumours under hypoxia.
doi:10.1038/srep20605
PMCID: PMC4742873  PMID: 26846992
10.  The Spermatophore in Glossina morsitans morsitans: Insights into Male Contributions to Reproduction 
Scientific Reports  2016;6:20334.
Male Seminal Fluid Proteins (SFPs) transferred during copulation modulate female reproductive physiology and behavior, impacting sperm storage/use, ovulation, oviposition, and remating receptivity. These capabilities make them ideal targets for developing novel methods of insect disease vector control. Little is known about the nature of SFPs in the viviparous tsetse flies (Diptera: Glossinidae), vectors of Human and Animal African trypanosomiasis. In tsetse, male ejaculate is assembled into a capsule-like spermatophore structure visible post-copulation in the female uterus. We applied high-throughput approaches to uncover the composition of the spermatophore in Glossina morsitans morsitans. We found that both male accessory glands and testes contribute to its formation. The male accessory glands produce a small number of abundant novel proteins with yet unknown functions, in addition to enzyme inhibitors and peptidase regulators. The testes contribute sperm in addition to a diverse array of less abundant proteins associated with binding, oxidoreductase/transferase activities, cytoskeletal and lipid/carbohydrate transporter functions. Proteins encoded by female-biased genes are also found in the spermatophore. About half of the proteins display sequence conservation relative to other Diptera, and low similarity to SFPs from other studied species, possibly reflecting both their fast evolutionary pace and the divergent nature of tsetse’s viviparous biology.
doi:10.1038/srep20334
PMCID: PMC4742874  PMID: 26847001
11.  Health governance in Sub-Saharan Africa 
Global Social Policy  2015;15(3):345-348.
doi:10.1177/1468018115600123d
PMCID: PMC4639823  PMID: 26635505
12.  Mass Spectrometric Immunoassay for Quantitative Determination of Transthyretin and its Variants 
Proteomics  2011;11(18):3633-3641.
Transthyretin (TTR, or prealbumin) is a tetrameric protein found in plasma and cerebrospinal fluid. Its major role is to transport thyroid hormones (thyroxin-T4) and retinol (through association with retinol-binding protein). TTR has been studied extensively, due to the great number of point mutations that result in sequence heterogeneity. Many of these variants are associated with pathological conditions that result in extracellular deposition of amyloid fibers in tissues. In this work, we have developed a rapid mass spectrometric immunoassay for determination and quantification of TTR and its variants from human serum and plasma samples. The assay was fully characterized in terms of its precision, linearity and recovery characteristics. The new assay was also compared with a conventional TTR ELISA. Furthermore, we have applied the optimized method to analyze transthyretin and its modifications in 44 human plasma samples, and in the process, optimized a method for TTR proteolytic digestion and identification of point mutations.
doi:10.1002/pmic.201100023
PMCID: PMC4599786  PMID: 21751365
transthyretin; immunoassay; mass spectrometry; plasma; quantification; trypsin
13.  On the bistable zone of milling processes 
A modal-based model of milling machine tools subjected to time-periodic nonlinear cutting forces is introduced. The model describes the phenomenon of bistability for certain cutting parameters. In engineering, these parameter domains are referred to as unsafe zones, where steady-state milling may switch to chatter for certain perturbations. In mathematical terms, these are the parameter domains where the periodic solution of the corresponding nonlinear, time-periodic delay differential equation is linearly stable, but its domain of attraction is limited due to the existence of an unstable quasi-periodic solution emerging from a secondary Hopf bifurcation. A semi-numerical method is presented to identify the borders of these bistable zones by tracking the motion of the milling tool edges as they might leave the surface of the workpiece during the cutting operation. This requires the tracking of unstable quasi-periodic solutions and the checking of their grazing to a time-periodic switching surface in the infinite-dimensional phase space. As the parameters of the linear structural behaviour of the tool/machine tool system can be obtained by means of standard modal testing, the developed numerical algorithm provides efficient support for the design of milling processes with quick estimates of those parameter domains where chatter can still appear in spite of setting the parameters into linearly stable domains.
doi:10.1098/rsta.2014.0409
PMCID: PMC4549941  PMID: 26303918
delay; time-periodic; milling; torus; bistable; chatter
14.  Modal testing for model validation of structures with discrete nonlinearities 
Model validation using data from modal tests is now widely practiced in many industries for advanced structural dynamic design analysis, especially where structural integrity is a primary requirement. These industries tend to demand highly efficient designs for their critical structures which, as a result, are increasingly operating in regimes where traditional linearity assumptions are no longer adequate. In particular, many modern structures are found to contain localized areas, often around joints or boundaries, where the actual mechanical behaviour is far from linear. Such structures need to have appropriate representation of these nonlinear features incorporated into the otherwise largely linear models that are used for design and operation. This paper proposes an approach to this task which is an extension of existing linear techniques, especially in the testing phase, involving only just as much nonlinear analysis as is necessary to construct a model which is good enough, or ‘valid’: i.e. capable of predicting the nonlinear response behaviour of the structure under all in-service operating and test conditions with a prescribed accuracy. A short-list of methods described in the recent literature categorized using our framework is given, which identifies those areas in which further development is most urgently required.
doi:10.1098/rsta.2014.0410
PMCID: PMC4549942  PMID: 26303924
nonlinear; modal testing; model upgrading; model updating; model validation
16.  Lung recruitment strategies 
Italian Journal of Pediatrics  2015;41(Suppl 1):A13.
doi:10.1186/1824-7288-41-S1-A13
PMCID: PMC4595569
18.  Neonatal renal venous and arterial thrombosis 
Italian Journal of Pediatrics  2015;41(Suppl 1):A24.
doi:10.1186/1824-7288-41-S1-A24
PMCID: PMC4595572
19.  Interval Graph Limits 
Annals of combinatorics  2012;17(1):27-52.
We work out a graph limit theory for dense interval graphs. The theory developed departs from the usual description of a graph limit as a symmetric function W (x, y) on the unit square, with x and y uniform on the interval (0, 1). Instead, we fix a W and change the underlying distribution of the coordinates x and y. We find choices such that our limits are continuous. Connections to random interval graphs are given, including some examples. We also show a continuity result for the chromatic number and clique number of interval graphs. Some results on uniqueness of the limit description are given for general graph limits.
doi:10.1007/s00026-012-0175-0
PMCID: PMC4578824  PMID: 26405368
interval graphs; graph limits; intersection graphs
20.  Flexible transition metal dichalcogenide nanosheets for band-selective photodetection 
Nature Communications  2015;6:8063.
The photocurrent conversions of transition metal dichalcogenide nanosheets are unprecedentedly impressive, making them great candidates for visible range photodetectors. Here we demonstrate a method for fabricating micron-thick, flexible films consisting of a variety of highly separated transition metal dichalcogenide nanosheets for excellent band-selective photodetection. Our method is based on the non-destructive modification of transition metal dichalcogenide sheets with amine-terminated polymers. The universal interaction between amine and transition metal resulted in scalable, stable and high concentration dispersions of a single to a few layers of numerous transition metal dichalcogenides. Our MoSe2 and MoS2 composites are highly photoconductive even at bending radii as low as 200 μm on illumination of near infrared and visible light, respectively. More interestingly, simple solution mixing of MoSe2 and MoS2 gives rise to blended composite films in which the photodetection properties were controllable. The MoS2/MoSe2 (5:5) film showed broad range photodetection suitable for both visible and near infrared spectra.
Transition metal dichalgogenide sheets prepared by liquid phase exfoliation can be limited in terms of scalability. Here, Velusamy et al. use a scalable liquid phase exfoliation process to fabricate micrometre thick composite nanosheets with amine-terminated polymers, which exhibit photo-detective properties.
doi:10.1038/ncomms9063
PMCID: PMC4569699  PMID: 26333531
21.  Protective Factors Associated with Fewer Multiple Problem Behaviors Among Homeless/Runaway Youth 
Although homeless youth exhibit numerous problem behaviors, protective factors that can be targeted and modified by prevention programs to decrease the likelihood of involvement in risky behaviors are less apparent. The current study tested a model of protective factors for multiple problem behavior in a sample of 474 homeless youth (42% girls; 83% minority) ages 12 to 24 years. Higher levels of problem solving and planning skills were strongly related to lower levels of multiple problem behaviors in homeless youth, suggesting both the positive impact of preexisting personal assets of these youth and important programmatic targets for further building their resilience and decreasing problem behaviors. Indirect relationships between the background factors of self-esteem and social support and multiple problem behaviors were significantly mediated through protective skills. The model suggests that helping youth enhance their skills in goal setting, decision making, and self-reliant coping could lessen a variety of problem behaviors commonly found among homeless youth.
doi:10.1080/15374416.2011.614581
PMCID: PMC4562907  PMID: 22023279
22.  Psychotherapy Credibility Ratings: Patient Predictors of Credibility and the Relation of Credibility to Therapy Outcome 
Very little is known about what factors may influence credibility ratings. The current investigation examined the relation between credibility ratings for adult psychotherapies and a variety of patient factors as well as the relation between credibility ratings and subsequent symptom change. A pooled study database that included studies evaluating the efficacy of cognitive and psychodynamic therapies for a variety of disorders was used. For all studies, a 3-item credibility scale was administered at session 2. Early symptom change, expectation of improvement, demographic characteristics, clinical measures, and functioning and interpersonal measures were used to predict credibility at session 2. We found that early symptom improvement was significantly associated with higher credibility ratings at session 2; higher ages, higher levels of education, and lower expectations of improvement were associated with lower credibility ratings at session 2; and credibility ratings predicted subsequent symptom improvement.
doi:10.1080/10503307.2013.847988
PMCID: PMC4560353  PMID: 24219179
23.  EVALUATION OF ENGINEERING CONTROLS FOR THE MIXING OF FLAVORINGS CONTAINING DIACETYL AND OTHER VOLATILE INGREDIENTS 
Exposures to diacetyl, a primary ingredient of butter flavoring, have been shown to cause respiratory disease among workers who mix flavorings. This study focused on evaluating ventilation controls designed to reduce emissions from the flavor mixing tanks, the major source of diacetyl in the plants. Five exhaust hood configurations were evaluated in the laboratory: standard hinged lid-opened, standard hinged lid-closed, hinged lid-slotted, dome with 38-mm gap, and dome with 114-mm gap. Tracer gas tests were performed to evaluate quantitative capture efficiency for each hood. A perforated copper coil was used to simulate an area source within the 1.2-meter diameter mixing tank. Capture efficiencies were measured at four hood exhaust flow rates (2.83, 5.66, 11.3, and 17.0 cubic meters per minute) and three cross draft velocities (0, 30, and 60 meters per minute). All hoods evaluated performed well with capture efficiencies above 90% for most combinations of exhaust volume and cross drafts. The standard hinged lid was the least expensive to manufacture and had the best average capture efficiency (over 99%) in the closed configuration for all exhaust flow rates and cross drafts. The hinged lid-slotted hood had some of the lowest capture efficiencies at the low exhaust flow rates compared to the other hood designs. The standard hinged lid performed well, even in the open position, and it provided a flexible approach to controlling emissions from mixing tanks. The dome hood gave results comparable to the standard hinged lid but it is more expensive to manufacture. The results of the study indicate that emissions from mixing tanks used in the production of flavorings can be controlled using simple inexpensive exhaust hoods.
doi:10.1080/15459624.2014.904517
PMCID: PMC4556953  PMID: 24649880
mixing workers; exhaust hood; diacetyl; tracer gas testing; emission control; mixing tank
25.  Personality Assessment in the Diagnostic Manuals: On Mindfulness, Multiple Methods, and Test Score Discontinuities 
Journal of personality assessment  2015;97(5):446-455.
Recent controversies have illuminated the strengths and limitations of different frameworks for conceptualizing personality pathology (e.g., trait perspectives, categorical models), and stimulated debate regarding how best to diagnose personality disorders (PDs) in DSM-5, and in other diagnostic systems (i.e., the International Classification of Diseases, the Psychodynamic Diagnostic Manual). In this article I argue that regardless of how PDs are conceptualized and which diagnostic system is employed, multi-method assessment must play a central role in PD diagnosis. By complementing self-reports with evidence from other domains (e.g., performance-based tests), a broader range of psychological processes are engaged in the patient, and the impact of self-perception and self-presentation biases may be better understood. By providing the assessor with evidence drawn from multiple modalities, some of which provide converging patterns and some of which yield divergent results, the assessor is compelled to engage this evidence more deeply. The mindful processing that ensues can help minimize the deleterious impact of naturally occurring information processing bias and distortion on the part of the clinician (e.g., heuristics, attribution errors), bringing greater clarity to the synthesis and integration of assessment data.
doi:10.1080/00223891.2015.1027346
PMCID: PMC4545313  PMID: 25856565

Results 1-25 (276)