Miracle-dz/UniFAR-FTUs huggingface dataset:
Antagonism screen for inhibitors of bacterial cell wall biogenesis uncovers an inhibitor of undecaprenyl diphosphate synthase

Significance Small molecule probes have proved indispensable in dissecting bacterial systems. Their combinations have further expanded their utility as tools by enabling the study of interacting pathways. As such, screens for synergy between compounds have been widely used to reveal functional connections among cellular components. The utility of antagonism, however, has largely been overlooked. This study highlights the value of antagonistic interactions in elucidating genetic networks and mechanisms of drug action. Herein, we report on the discovery of clomiphene, an inhibitor of bacterial cell wall synthesis, uncovered through a systematic screen for antagonism. The discovery of clomiphene shed light on the pathways of cell wall biogenesis and, importantly, represents a new promising lead for the fight against infection. Drug combinations are valuable tools for studying biological systems. Although much attention has been given to synergistic interactions in revealing connections between cellular processes, antagonistic interactions can also have tremendous value in elucidating genetic networks and mechanisms of drug action. Here, we exploit the power of antagonism in a high-throughput screen for molecules that suppress the activity of targocil, an inhibitor of the wall teichoic acid (WTA) flippase in Staphylococcus aureus. Well-characterized antagonism within the WTA biosynthetic pathway indicated that early steps would be sensitive to this screen; however, broader interactions with cell wall biogenesis components suggested that it might capture additional targets. A chemical screening effort using this approach identified clomiphene, a widely used fertility drug, as one such compound. Mechanistic characterization revealed the target was the undecaprenyl diphosphate synthase, an enzyme that catalyzes the synthesis of a polyisoprenoid essential for both peptidoglycan and WTA synthesis. The work sheds light on mechanisms contributing to the observed suppressive interactions of clomiphene and in turn reveals aspects of the biology that underlie cell wall synthesis in S. aureus. Further, this effort highlights the utility of antagonistic interactions both in high-throughput screening and in compound mode of action studies. Importantly, clomiphene represents a lead for antibacterial drug discovery.
Generation and propagation of a picosecond acoustic pulse at a buried interface: time-resolved x-ray diffraction measurements.

We report on the propagation of coherent acoustic wave packets in (001) surface oriented Al0.3Ga0. 7As/GaAs heterostructure, generated through localized femtosecond photoexcitation of the GaAs. Transient structural changes in both the substrate and film are measured with picosecond time-resolved x-ray diffraction. The data indicate an elastic response consisting of unipolar compression pulses of a few hundred picosecond duration traveling along [001] and [001] directions that are produced by predominately impulsive stress. The transmission and reflection of the strain pulses are in agreement with an acoustic mismatch model of the heterostructure and free-space interfaces.
Cranial neural‐crest migration and chondrogenic fate in the oriental fire‐bellied toad Bombina orientalis: Defining the ancestral pattern of head development in anuran amphibians

We assess cranial neural‐crest cell migration and contributions to the larval chondrocranium in the phylogenetically basal and morphologically generalized anuran Bombina orientalis (Bombinatoridae). Methods used include microdissection, scanning electron microscopy, and vital dye labeling, in conjunction with confocal and fluorescence microscopy. Cranial neural‐crest cells begin migrating before neural‐fold closure and soon form three primary streams. These streams contribute to all cranial cartilages except two medial components of the hyobranchial skeleton (basihyal and basibranchial cartilages), the posterior portion of the trabecular plate, and the otic capsule, the embryonic origin of which is unknown. Chondrogenic fate is regionalized within the cranial neural folds, with the anterior regions contributing to anterior cartilages and the posterior regions to posterior cartilages. A neural‐crest contribution also was consistently observed in several cranial nerves and the connective tissue component of many cranial muscles. Notwithstanding minor differences among species in the initial configuration of migratory streams, cranial neural‐crest migration and chondrogenic potential in metamorphosing anurans seem to be highly stereotyped and evolutionarily conservative. This includes a primary role for the neural crest in the evolutionary origin of the paired suprarostral and infrarostral cartilages, two prominent caenogenetic features of the rostral skull unique to anuran larvae. Our results provide a model of the ancestral pattern of embryonic head development in anuran amphibians. This model can serve as a basis for examining the ontogenetic mechanisms that underlie the diversity of cranial morphology and development displayed by living frogs, as well as the evolutionary consequences of this diversity. © 1996 Wiley‐Liss, Inc.
'Antifreeze' glycoproteins from polar fish.

Antifreeze glycoproteins (AFGPs) constitute the major fraction of protein in the blood serum of Antarctic notothenioids and Arctic cod. Each AFGP consists of a varying number of repeating units of (Ala-Ala-Thr)n, with minor sequence variations, and the disaccharide beta-D-galactosyl-(1-->3)-alpha-N-acetyl-D-galactosamine joined as a glycoside to the hydroxyl oxygen of the Thr residues. These compounds allow the fish to survive in subzero ice-laden polar oceans by kinetically depressing the temperature at which ice grows in a noncolligative manner. In contrast to the more widely studied antifreeze proteins, little is known about the mechanism of ice growth inhibition by AFGPs, and there is no definitive model that explains their properties. This review summarizes the structural and physical properties of AFGPs and advances in the last decade that now provide opportunities for further research in this field. High field NMR spectroscopy and molecular dynamics studies have shown that AFGPs are largely unstructured in aqueous solution. While standard carbohydrate degradation studies confirm the requirement of some of the sugar hydroxyls for antifreeze activity, the importance of following structural elements has not been established: (a) the number of hydroxyls required, (b) the stereochemistry of the sugar hydroxyls (i.e. the requirement of galactose as the sugar), (c) the acetamido group on the first galactose sugar, (d) the stereochemistry of the beta-glycosidic linkage between the two sugars and the alpha-glycosidic linkage to Thr, (e) the requirement of a disaccharide for activity, and (f) the Ala and Thr residues in the polypeptide backbone. The recent successful synthesis of small AFGPs using solution methods and solid-phase chemistry provides the opportunity to perform key structure-activity studies that would clarify the important residues and functional groups required for activity. Genetic studies have shown that the AFGPs present in the two geographically and phylogenetically distinct Antarctic notothenioids and Arctic cod have evolved independently, in a rare example of convergent molecular evolution. The AFGPs exhibit concentration dependent thermal hysteresis with maximum hysteresis (1.2 degrees C at 40 mg x mL-1) observed with the higher molecular mass glycoproteins. The ability to modify the rate and shape of crystal growth and protect cellular membranes during lipid-phase transitions have resulted in identification of a number of potential applications of AFGPs as food additives, and in the cryopreservation and hypothermal storage of cells and tissues.
Extraction of permeability from time‐lapse seismic data

Two formulae are developed for estimating horizontal permeability directly from maps of 4D seismic signatures. The choice of the formula used depends on whether the seismic is dominated by changes of pressure or saturation. However, pressure derived from time‐lapse seismic, or seismic amplitudes controlled predominantly by pressure are to be preferred for optimal ‘illumination’ of the reservoir. The permeability is predicted to be dependent on porosity but weighted by a 4D term related to the magnitude and spatial gradient of the 4D signature. Tests performed on model‐based synthetic seismic data affirm the validity and accuracy of this approach. Application to field data from the UK continental shelf reveals a large‐scale permeability variation similar to the existing simulation model, but with additional fine‐scale detail. The technique thus has the potential of providing extra information with which to update the simulation model. The resultant permeability estimates have been successfully ground‐truthed against the results of two well tests. As non‐repeatable noise in the time‐lapse seismic data diminishes with improved 4D‐related acquisition, it will become increasingly possible to make robust permeability estimates using this approach.
Federal Reserve Bank of Minneapolis Research Department Staff Report 422 Momentum Traders in the Housing Market: Survey Evidence and a Search Model *

This paper studies household beliefs during the recent US housing boom. To characterize the heterogeneity in households' views about housing and the economy, we perform a cluster analysis on survey responses at different stages of the boom. The estimation always finds a small cluster of households who believe it is a good time to buy a house because house prices will rise further. The size of this " momentum " cluster doubled towards the end of the boom. We also provide a simple search model of the housing market to show how a small number of optimistic investors can have a large effect on prices without buying a large share of the housing stock. We thank Bob Hall and Luigi Guiso for comments. The views expressed herein are those of the authors and not necessarily those of the Federal Reserve Bank of Minneapolis or the Federal Reserve System.
Incidence Rates and Trend of Serious Farm-Related Injury in Minnesota, 2000–2011

ABSTRACT Only about 2% of Minnesota’s workers were employed in agriculture for the years 2005–2012, this small portion of the workforce accounted for 31% of the 563 work-related deaths that occurred in Minnesota during that same time period. Agricultural fatalities in Minnesota and elsewhere are well documented; however, nonfatal injuries are not. To explore the burden of injury, Minnesota hospital discharge data were used to examine rates and trends of farm injury for the years 2000–2011. Cases were identified through the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), injury codes and external cause of injury codes (E codes). Probable cases were defined as E code E849.1 (occurred on a farm) or E919.0 (involving agricultural machinery). Possible cases were based on five less specific E codes primarily involving animals or pesticides. Multiple data sources were used to estimate the agricultural population. An annual average of over 500 cases was identified as probable, whereas 2,000 cases were identified as possible. Trend analysis of all identified cases indicated a small but significant average annual increase of 1.5% for the time period 2000–2011. Probable cases were predominantly male (81.5%), whereas possible cases were predominantly female (63.9%). The average age of an injury case was 38.5 years, with the majority of injuries occurring in late summer and fall months. Despite the undercount of less serious injuries, hospital discharge data provide a meaningful data source for the identification and surveillance of nonfatal agricultural injuries. These methods could be utilized by other states for ongoing surveillance for nonfatal agricultural injuries.
Immunohistochemical Study of Melanocyte–Melanocyte Stem Cell lineage in Vitiligo; A Clue to Interfollicular Melanocyte Stem Cell Reservoir

ABSTRACT There has been a long lasting controversy over whether melanocytes (MCs) in vitiligo are actually lost or still present but functionally inactive. We aimed to evaluate the MC cell lineage in follicular and interfollicular vitiliginous epidermis through immunohistochemical localization of Human Melanoma Black-45 (HMB-45) and Tyrosinase Related Protein 2 (TRP2) and to correlate it with clinicopathologic parameters. Using immunohistochemical techniques, skin biopsies from 50 vitiligo patients and 20 age- and gender-matched healthy subjects were examined. Differentiated active MCs were detected in 44% of interfollicular epidermis (IFE) and 46.7% of follicular epidermis (FE) in lesional skin. Melanocyte precursors/stem cells were detected in 54% of IFE and 63.3% of FE in lesional skin. Melanocyte precursors/stem cells of IFE were significantly associated with residual melanin pigment (p = 0.007) and with absence of angiogenesis (p = 0.05). HMB-45 percentage of expression in IFE was positively correlated with MC precursors/stem cells percentage in FE (r = +0.65, p < 0.001) and IFE (r = +0.33, p = 0.01). Melanocyte precursors/stem cells positivity (p < 0.001) was progressively decreasing with advanced histopathologic grading. There was no significant association between interfollicular or follicular expression of HMB-45, TRP2 or MC precursors/stem cells and the clinical type of vitiligo or its duration. In conclusion, functioning MCs may exist in vitiligo. The presence of MC precursors/stem cells in IFE may provide an additional reservoir needed for repigmentation.
Arctic aerosol size-segregated chemical observations in relation to ozone depletion during Polar Sunrise Experiment 1992

During Polar Sunrise Experiment 1992 at Alert in the Canadian high Arctic, size-fractionated observations of aerosol constituents (halogens, Na, V, As, Sb, Zn, Al, Ca, SO4=, Sm, K, Mn, and Mg) were made using a low-pressure cascade impactor and a high-volume virtual impactor (HVVI). Over 80% of the mass of V, Br, I, As, Sb, Zn, and SO4= was in particles <2.5 μm diameter. In contrast to SO4=, NO3− has more mass in larger particles. Similarly, Cl peaked in larger particles (1.72 to 6.0 μm) than Na (0.49 and 1.72 μr). Both of these effects are likely caused by reactions of sulphate acids with salts of nitrates and chloride in submicrometer particles and the volatilization of HNO3 and HCl. For fine particles (diameter <2.5 μm), observations of relatively, nonvolatile primary particulate elements (Na, V, Mn) with the two measurement devices agreed within analytical uncertainty. In contrast, they did not agree well for the more volatile halogens. The HVVI always recorded higher. Sea-salt enrichment factors of Cl (EFs s) referenced to Na for the HVVI data showed enrichment (1.2 to 1.8) in both fine and coarse aerosols during January. Thereafter, EFss averaged 0.92 and 0.57 for coarse and fine fractions, respectively, and were well correlated with each other. In contrast, EFss on fine particles collected with the cascade impactor were considerably lower (0.18 to 0.44), indicating volatilization of Cl within the device. A principal component analysis of fine particle (<2.5 μm) constituents from the HVVI identified six aerosol components consisting of anthropogenic (Mn, As, Sb, V, Zn, Al), sea salt (Cl, Na), iodine-bromine (I, Br), photochemical (Br, −O3), soil (Ca, Al), and one loaded solely by Sm. For the whole period, there was a strong anticorrelation between O3 and aerosol Br but not with the other halogens. In this study, iodine was significantly linearly correlated with the square root of the Br concentration. It showed a weak anticorrelation with O3 only after polar sunrise but not before.
Modelling FTIR spectral sata with Type-I and Type-II fuzzy sets for breast cancer grading

Breast cancer is one of the most frequently occurring cancers amongst women throughout the world. After the diagnosis of the disease, monitoring its progression is important in predicting the chances of long term survival of patients. The Nottingham Prognostic Index (NPI) is one of the most common indices used to categorise the patients into different groups depending upon the severity of the disease. One of the key factors of this index is cancer grade which is determined by pathologists who examine cell samples under a microscope. This manual method has a higher chance of false classification and may lead to incorrect treatment of patients. There is a need to develop automated methods that employ advanced computational methods to help pathologists in making a decision regarding the classification of breast cancer grade. Fourier transform infra-red spectroscopy (FTIR) is one of the relatively new techniques that has been used for diagnosis of various cancer types with advanced computational methods in the literature. In this thesis we examine the use of advanced fuzzy methods with the FTIR spectral data sets to develop a model prototype that can help clinicians with breast cancer grading. Initial work is focussed on using the commonly used clustering algorithms k-means and fuzzy c-means with principal component analysis on different cancer spectral data sets to explore the complexities within them. After that, a novel model based on Type-II fuzzy logic is developed for use on a complex breast cancer FTIR spectral data set that can help clinicians classify breast cancer grades. The data set used for the purpose consists of multiple cases of each grade. We consider two types of uncertainty, one within the spectra of a single case of a grade (intra -case) and other when comparing it with other cases of same grade (inter-case). Features have been extracted in terms of interval data from various peaks and troughs. The interval data from the features has been used to create Type-I fuzzy sets for each case. After that the Type-I fuzzy sets are combined to create zSlices based General Type-II fuzzy sets for each feature for each grade. The created benchmark fuzzy sets are then used as prototypes for classification of unseen spectral data. Type-I fuzzy sets are created for unseen spectral data and then compared against the benchmark prototype Type-II fuzzy sets for each grade using a similarity measure. The best match based on the calculated similarity scores is assigned as the resultant grade. The novel model is tested on an independent spectral data set of oral cancer patients. Results indicate that the model was able to successfully construct prototype fuzzy sets for the data set, and provide in-depth information regarding the complexities of the data set as well as helping in classification of the data.
Numerical simulation of acoustic emission in brittle rocks by two-dimensional finite-discrete element analysis

Erratum: Numerical simulation of acoustic emission in brittle rocks by two-dimensional finite-discrete element analysis By A. Lisjak,1 Q. Liu,2 Q. Zhao,1 O. K. Mahabadi1 and G. Grasselli1 1Department of Civil Engineering, University of Toronto, 35 St George Street, Toronto, Ontario M5S 1A4, Canada. E-mail: andrea.lisjak@utoronto.ca 2Department of Physics, University of Toronto, 60 St George Street, Toronto, Ontario M5S 1A7, Canada
Alteration of the Glucagon Axis in GPR120 (FFAR4) Knockout Mice

Background: GPR120 (FFAR4) is a GPCR activated by long chain fatty acids. Results: Palmitate- and DHA-stimulated glucagon secretion is markedly reduced from GPR120 KO islets. Conclusion: GPR120 is a nutrient sensor that is activated endogenously by both saturated and unsaturated long chain fatty acids. Significance: Targeting GPR120 for diabetes may impact glucose homeostasis in part through altering glucagon secretion and islet function. GPR40 (FFAR1) and GPR120 (FFAR4) are G-protein-coupled receptors (GPCRs) that are activated by long chain fatty acids (LCFAs). GPR40 is expressed at high levels in islets and mediates the ability of LCFAs to potentiate glucose-stimulated insulin secretion (GSIS). GPR120 is expressed at high levels in colon, adipose, and pituitary, and at more modest levels in pancreatic islets. The role of GPR120 in islets has not been explored extensively. Here, we confirm that saturated (e.g. palmitic acid) and unsaturated (e.g. docosahexaenoic acid (DHA)) LCFAs engage GPR120 and demonstrate that palmitate- and DHA-potentiated glucagon secretion are greatly reduced in isolated GPR120 KO islets. Remarkably, LCFA potentiated glucagon secretion is similarly reduced in GPR40 KO islets. Compensatory changes in mRNA expression of GPR120 in GPR40 KO islets, and vice versa, do not explain that LCFA potentiated glucagon secretion seemingly involves both receptors. LCFA-potentiated GSIS remains intact in GPR120 KO islets. Consistent with previous reports, GPR120 KO mice are hyperglycemic and glucose intolerant; however, our KO mice display evidence of a hyperactive counter-regulatory response rather than insulin resistance during insulin tolerance tests. An arginine stimulation test and a glucagon challenge confirmed both increases in glucagon secretion and liver glucagon sensitivity in GPR120 KO mice relative to WT mice. Our findings demonstrate that GPR120 is a nutrient sensor that is activated endogenously by both saturated and unsaturated long chain fatty acids and that an altered glucagon axis likely contributes to the impaired glucose homeostasis observed in GPR120 KO mice.
Reducing FLI1 Levels in the MRL/lpr Lupus Mouse Model Impacts T Cell Function by Modulating Glycosphingolipid Metabolism

Systemic Lupus erythematosus (SLE) is an autoimmune disease caused, in part, by abnormalities in cells of the immune system including B and T cells. Genetically reducing globally the expression of the ETS transcription factor FLI1 by 50% in two lupus mouse models significantly improves disease measures and survival through an unknown mechanism. In this study we analyze the effects of reducing FLI1 in the MRL/lpr lupus prone model on T cell function. We demonstrate that adoptive transfer of MRL/lpr Fli1 +/+ or Fli1 +/- T cells and B cells into Rag1-deficient mice results in significantly decreased serum immunoglobulin levels in animals receiving Fli1 +/- lupus T cells compared to animals receiving Fli1 +/+ lupus T cells regardless of the genotype of co-transferred lupus B cells. Ex vivo analyses of MRL/lpr T cells demonstrated that Fli1 +/- T cells produce significantly less IL-4 during early and late disease and exhibited significantly decreased TCR-specific activation during early disease compared to Fli1 +/+ T cells. Moreover, the Fli1 +/- T cells expressed significantly less neuraminidase 1 (Neu1) message and decreased NEU activity during early disease and significantly decreased levels of glycosphingolipids during late disease compared to Fli1 +/+ T cells. FLI1 dose-dependently activated the Neu1 promoter in mouse and human T cell lines. Together, our results suggest reducing FLI1 in lupus decreases the pathogenicity of T cells by decreasing TCR-specific activation and IL-4 production in part through the modulation of glycosphingolipid metabolism. Reducing the expression of FLI1 or targeting the glycosphingolipid metabolic pathway in lupus may serve as a therapeutic approach to treating lupus.