Miracle-dz/UniFAR-FTUs huggingface dataset:
New IBD genetics: common pathways with other diseases

Complex disease genetics has been revolutionised in recent years by the advent of genome-wide association (GWA) studies. The chronic inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis have seen notable successes culminating in the discovery of 99 published susceptibility loci/genes (71 Crohn's disease; 47 ulcerative colitis) to date. Approximately one-third of loci described confer susceptibility to both Crohn's disease and ulcerative colitis. Amongst these are multiple genes involved in IL23/Th17 signalling (IL23R, IL12B, JAK2, TYK2 and STAT3), IL10, IL1R2, REL, CARD9, NKX2.3, ICOSLG, PRDM1, SMAD3 and ORMDL3. The evolving genetic architecture of IBD has furthered our understanding of disease pathogenesis. For Crohn's disease, defective processing of intracellular bacteria has become a central theme, following gene discoveries in autophagy and innate immunity (associations with NOD2, IRGM, ATG16L1 are specific to Crohn's disease). Genetic evidence has also demonstrated the importance of barrier function to the development of ulcerative colitis (HNF4A, LAMB1, CDH1 and GNA12). However, when the data are analysed in more detail, deeper themes emerge including the shared susceptibility seen with other diseases. Many immune-mediated diseases overlap in this respect, paralleling the reported epidemiological evidence. However, in several cases the reported shared susceptibility appears at odds with the clinical picture. Examples include both type 1 and type 2 diabetes mellitus. In this review we will detail the presently available data on the genetic overlap between IBD and other diseases. The discussion will be informed by the epidemiological data in the published literature and the implications for pathogenesis and therapy will be outlined. This arena will move forwards very quickly in the next few years. Ultimately, we anticipate that these genetic insights will transform the landscape of common complex diseases such as IBD.
The IL-6/STAT3 Signaling Pathway Is an Early Target of Manuka Honey-Induced Suppression of Human Breast Cancer Cells

There is renewed interest in the potential use of natural compounds in cancer therapy. Previously, we demonstrated the anti-tumor properties of manuka honey (MH) against several cancers. However, the underlying mechanism and molecular targets of this activity remain unknown. For this study, the early targets of MH and its modulatory effects on proliferation, invasiveness, and angiogenic potential were investigated using two human breast cancer cell lines, the triple-negative MDA-MB-231 cells and estrogen receptor-positive MCF-7 cells, and the non-neoplastic breast epithelial MCF-10A cell line. Exposure to MH at concentrations of 0.3–1.25% (w/v) induced a dose-dependent inhibition of the proliferation of MDA-MB-231 and MCF-7, but not MCF-10A, cells. This inhibition was independent of the sugar content of MH as a solution containing equivalent concentrations of its three major sugars failed to inhibit cell proliferation. At higher concentrations (>2.5%), MH was found to be generally deleterious to the growth of all three cell lines. MH induced apoptosis of MDA-MB-231 cells through activation of caspases 8, 9, 6, and 3/7 and this correlated with a loss of Bcl-2 and increased Bax protein expression in MH-treated cells. Incubation with MH induced a time-dependent translocation of cytochrome c from mitochondria to the cytosol and Bax translocation from the cytosol into the mitochondria. MH also induced apoptosis of MCF-7 cells via the activation of caspases 9 and 6. Low concentrations of MH (0.03–1.25% w/v) induced a rapid reduction in tyrosine-phosphorylated STAT3 (pY-STAT3) in MDA-MB-231 and MCF-7 cells. Maximum inhibition of pY-STAT3 was observed at 1 h with a loss of >80% and coincided with decreased interleukin-6 (IL-6) production. Moreover, MH inhibited the migration and invasion of MDA-MB-231 cells as well as the angiogenic capacity of human umbilical vein endothelial cells. Our findings identify multiple functional pathways affected by MH in human breast cancer and highlight the IL-6/STAT3 signaling pathway as one of the earliest potential targets in this process.
Serum retinol in post‐partum mothers and newborns from an impoverished South African community where liver is frequently eaten and vitamin A deficiency is absent

Serum retinol was assessed in mothers and newborns from an impoverished South African community where liver is frequently eaten and vitamin A deficiency known to be absent. Paired cord and maternal blood (n = 201) were collected after delivery and analysed for serum retinol and C-reactive protein (CRP). Liver intake during pregnancy and intention to breastfeed were also assessed. Mean serum retinol was 1.03 µmol/L ± 0.40 in mothers and 0.73 ± 0.24 µmol/L in newborns, with 21.4% and 49.3% having serum retinol <0.70 µmol/L (<20 µg/dL), respectively. Raised CRP was found in 59.9% of mothers, with a significant negative correlation between serum retinol and CRP (r = -0.273; p < 0.0001). Liver was eaten by 87.6% of mothers, and 99% indicated their intention to breastfeed. Despite consumption of liver, serum retinol was low in both the mother and the newborn. The conventional cut-off for serum retinol, i.e. <0.70 µmol/L may therefore not apply for the mother and newborn in the period immediately after delivery. Serum retinol may be influenced by factors other than vitamin A status, e.g. the haemodilution of pregnancy, as well as the acute phase response induced by the birth process, as suggested by raised CRP in 60% of mothers. In the newborns, the low serum retinol is likely to increase rapidly, as liver is frequently eaten by mothers and practically all of them intended to breastfeed. Our results confirm the need for better indicators of vitamin A status or alternative cut-off values during this period.
Arachidonic Acid Stimulates a Novel Cocaine-Sensitive Cation Conductance Associated with the Human Dopamine Transporter

The dopamine transporter (DAT) exhibits several ionic currents that are either coupled to or uncoupled from the transport of substrate. Second messenger systems have been shown to modulate dopamine (DA) transport, however, the modulation of DAT-associated currents has not been studied in depth. Using the two-electrode voltage-clamp method to record from Xenopus oocytes expressing the human DAT, we examined the effects of arachidonic acid (AA) on membrane currents. AA (10–100 μm) stimulates a novel nonselective cation conductance seen only in oocytes expressing human DA transporter (hDAT). The AA-stimulated conductance is up to 50-fold greater than the current normally elicited by DA, but does not appear to arise from the modulation of previously described hDAT conductances, including the leak current and the current associated with electrogenic transport. In addition, DA dramatically potentiates and cocaine blocks the AA-stimulated DAT current. DA potentiates the AA-induced currents in the absence of sodium and chloride, indicating that these currents arise from processes distinct from those associated with substrate transport. The effects of AA were mimicked by other fatty acids with a rank order of potency correlated with their degree of unsaturation, suggesting that AA directly stimulates the novel cation current. Therefore, AA stimulation of this DAT-associated conductance may provide a novel mechanism for modulation of neuronal signaling.
Advanced Glycation End Products Enhance Macrophages Polarization into M1 Phenotype through Activating RAGE/NF-κB Pathway

Atherosclerotic lesions are accelerated in patients with diabetes. M1 (classically activated in contrast to M2 alternatively activated) macrophages play key roles in the progression of atherosclerosis. Since advanced glycation end products (AGEs) are major pathogenic factors and active inflammation inducers in diabetes mellitus, this study assessed the effects of AGEs on macrophage polarization. The present study showed that AGEs significantly promoted macrophages to express IL-6 and TNF-α. M1 macrophage markers such as iNOS and surface markers including CD11c and CD86 were significantly upregulated while M2 macrophage markers such as Arg1 and CD206 remained unchanged after AGEs stimulation. AGEs significantly increased RAGE expression in macrophages and activated NF-κB pathway, and the aforementioned effects were partly abolished by administration of anti-RAGE antibody or NF-κB inhibitor PDTC. In conclusion, our results suggest that AGEs enhance macrophage differentiation into proinflammatory M1 phenotype at least partly via RAGE/NF-κB pathway activation.
manuscript On Approximating Optimal Sampling Laws for Stochastically Constrained Simulation Optimization on Large Finite Sets

Nugroho Artadi Pujowidianto Department of Industrial and Systems Engineering, National University of Singapore, SINGAPORE, nugroho@nus.edu. sg Susan R. Hunter School of Operations Research and Information Engineering, Cornell University, Ithaca, NY 14853, USA, hunter@cornell.edu Raghu Pasupathy The Grado Department of Industrial and Systems Engineering, Virginia Tech, Blacksburg, VA 24061, USA, pasupath@vt.edu Loo Hay Lee Department of Industrial and Systems Engineering, National University of Singapore, SINGAPORE, iseleelh@. nus.edu. sg Chun-Hung Chen Systems Engineering and Operations Research, George Mason University, Fairfax, VA 22030, USA, cchen9@gmu.edu
Determination of Grain Quality Characters of Some Egyptian Rice Cultivars Under Low Levels of Nitrogen Fertilizer

Tow field experiments on rice crop (Oryza sativa, L.) were conducted during two summer growing seasons, 2016 and 2017 at the Experimental Farm of Rice Research and Training Center (RRTC); Sakha, Kafr El-Sheikh Egypt in cooperation with Rice Training and Technology Center (RTTC),Alexandria, Egypt to study grain quality traits of some Egyptian rice cultivars grown under low fertilizer levels . The results revealed that increasing nitrogen fertilization caused significant increase in the mean values of the most studied characters. In connection, decreasing such fertilizer levels to 50% of the recommended rates did not affect the mean values of some tested cultivars of most studied characters.
FINDSITELHM: A Threading-Based Approach to Ligand Homology Modeling

Ligand virtual screening is a widely used tool to assist in new pharmaceutical discovery. In practice, virtual screening approaches have a number of limitations, and the development of new methodologies is required. Previously, we showed that remotely related proteins identified by threading often share a common binding site occupied by chemically similar ligands. Here, we demonstrate that across an evolutionarily related, but distant family of proteins, the ligands that bind to the common binding site contain a set of strongly conserved anchor functional groups as well as a variable region that accounts for their binding specificity. Furthermore, the sequence and structure conservation of residues contacting the anchor functional groups is significantly higher than those contacting ligand variable regions. Exploiting these insights, we developed FINDSITELHM that employs structural information extracted from weakly related proteins to perform rapid ligand docking by homology modeling. In large scale benchmarking, using the predicted anchor-binding mode and the crystal structure of the receptor, FINDSITELHM outperforms classical docking approaches with an average ligand RMSD from native of ∼2.5 Å. For weakly homologous receptor protein models, using FINDSITELHM, the fraction of recovered binding residues and specific contacts is 0.66 (0.55) and 0.49 (0.38) for highly confident (all) targets, respectively. Finally, in virtual screening for HIV-1 protease inhibitors, using similarity to the ligand anchor region yields significantly improved enrichment factors. Thus, the rather accurate, computationally inexpensive FINDSITELHM algorithm should be a useful approach to assist in the discovery of novel biopharmaceuticals.
Cervical cancer screening with clinic-based Pap test versus home HPV test among Somali immigrant women in Minnesota: a pilot randomized controlled trial

Cervical cancer is more common in the Somali immigrant population than the general population in the United States (US). There are low rates of cervical cancer screening among Somali women. This study compares cervical cancer screening test completion rates for a home human papilloma virus (HPV) test and standard clinic Pap test. Sixty‐three Somali immigrant women aged 30–70 years who had not undergone cervical cancer screening within the past 3 years were randomly assigned to a home HPV test group (intervention) or a clinic Pap test group (control). Test completion rates were measured at 3 months. Univariate and multivariate logistic regression models were used to explore factors associated with test completion (intention‐to‐treat analysis). Participants in the HPV test group were 14 times more likely to complete the test compared to those in the Pap test group (P = 0.0002). Women who reported having friends/family members to talk about cancer screening were approximately three times more likely to complete any screening test than those who did not (P = 0.127) and participants who reported residing in the US longer were more likely to complete a screening test (P = 0.011). Future research should explore the potential of using the home‐based HPV test kits as an initial approach to cervical cancer screening. Impact: The use of a self‐sampling HPV kit has the potential to increase cervical cancer screening in under‐served communities in the US.
Effect of CYP2A6 Genetic Polymorphism on the Metabolic Conversion of Tegafur to 5-Fluorouracil and Its Enantioselectivity

Tegafur (FT), a prodrug of 5-fluorouracil, is a chiral molecule, a racemate of R- and S-isomers, and CYP2A6 plays an important role in the enantioselective metabolism of FT in human liver microsomes (R-FT >> S-FT). This study examined the enantioselective metabolism of FT by microsomes prepared from Sf9 cells expressing wild-type CYP2A6 and its variants (CYP2A6*7, *8, *10, and *11) that are highly prevalent in the Asian population. We also investigated the metabolism of coumarin and nicotine, both CYP2A6 probe drugs, in these variants. Enzyme kinetic analyses showed that CYP2A6.7 (I471T) and CYP2A6.10 (I471T and R485L) had markedly lower Vmax values for both enantiomers than wild-type enzyme (CYP2A6.1) and other variant enzymes, whereas Km values were higher in most of the variant enzymes for both enantiomers than CYP2A6.1. The ratios of Vmax and Km values for R-FT to corresponding values for S-FT (R/S ratio) were similar among enzymes, indicating little difference in enantioselectivity among the wild-type and variant enzymes. Similarly, both CYP2A6.7 and CYP2A6.10 had markedly lower Vmax values for coumarin 7-hydroxylase and nicotine C-oxidase activities than CYP2A6.1 and other variant enzymes, whereas Km values were higher in most of the variant enzymes for both activities than CYP2A6.1. In conclusion, the amino acid substitutions in CYP2A6 variants generally resulted in lower affinity for substrates, while Vmax values were selectively reduced in CYP2A6.7 and CYP2A6.10. Consistent R/S ratios among CYP2A6.1 and variant enzymes indicated that the amino acid substitutions had little effect on enantioselectivity in the metabolism of FT.
Marital status and survival after oesophageal cancer surgery: a population-based nationwide cohort study in Sweden

Objectives A beneficial effect of being married on survival has been shown for several cancer types, but is unclear for oesophageal cancer. The objective of this study was to clarify the potential influence of the marital status on the overall and disease-specific survival after curatively intended treatment of oesophageal cancer using a nationwide population-based design, taking into account the known major prognostic variables. Design Prospective, population-based cohort. Setting All Swedish hospitals performing surgery for oesophageal cancer during 2001–2005. Participants This study included 90% of all patients with oesophageal or junctional cancer who underwent surgical resection in Sweden in 2001–2005, with follow-up until death or the end of the study period (2012). Primary and secondary outcome measures Cox regression was used to estimate associations between the marital status and the 5-year overall and disease-specific mortality, expressed as HRs with 95% CIs, with adjustment for sex, age, tumour stage, histological type, complications, comorbidities and annual surgeon volume. Results Of all 606 included patients (80.4% men), 55.1% were married, 9.2% were remarried, 22.6% were previously married and 13% were never married. Compared with the married patients, the never married (HR 1.02, 95% CI 0.77 to 1.35), previously married (HR 0.90, 95% CI 0.71 to 1.15) and remarried patients (HR 0.79, 95% CI 0.55 to 1.13) had no increased overall 5-year mortality. The corresponding HRs for disease-specific survival, and after excluding the initial 90 days of surgery, were similar to the HRs for the overall survival. Conclusions This study showed no evidence of a better 5-year survival in married patients compared with non-married patients undergoing surgery for oesophageal cancer.
FINAL REPORT Prediction of Groundwater Quality Down-gradient of In Situ Permeable Treatment Barriers and Fully-remediated Source Zones ESTCP Project ER-0320 September 2008

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Rigidity of quantum steering and one-sided device-independent verifiable quantum computation

The relationship between correlations and entanglement has played a major role in understanding quantum theory since the work of Einstein et al (1935 Phys. Rev. 47 777–80). Tsirelson proved that Bell states, shared among two parties, when measured suitably, achieve the maximum non-local correlations allowed by quantum mechanics (Cirel’son 1980 Lett. Math. Phys. 4 93–100). Conversely, Reichardt et al showed that observing the maximal correlation value over a sequence of repeated measurements, implies that the underlying quantum state is close to a tensor product of maximally entangled states and, moreover, that it is measured according to an ideal strategy (Reichardt et al 2013 Nature 496 456–60). However, this strong rigidity result comes at a high price, requiring a large number of entangled pairs to be tested. In this paper, we present a significant improvement in terms of the overhead by instead considering quantum steering where the device of the one side is trusted. We first demonstrate a robust one-sided device-independent version of self-testing, which characterises the shared state and measurement operators of two parties up to a certain bound. We show that this bound is optimal up to constant factors and we generalise the results for the most general attacks. This leads us to a rigidity theorem for maximal steering correlations. As a key application we give a one-sided device-independent protocol for verifiable delegated quantum computation, and compare it to other existing protocols, to highlight the cost of trust assumptions. Finally, we show that under reasonable assumptions, the states shared in order to run a certain type of verification protocol must be unitarily equivalent to perfect Bell states.
Purinergic Modulation of Interleukin-1β Release from Microglial Cells Stimulated with Bacterial Endotoxin

Microglial cells express a peculiar plasma membrane receptor for extracellular ATP, named P2Z/P2X7 purinergic receptor, that triggers massive transmembrane ion fluxes and a reversible permeabilization of the plasma membrane to hydrophylic molecules of up to 900 dalton molecule weight and eventual cell death (Di Virgilio, F. 1995. Immunol. Today. 16:524–528). The physiological role of this newly cloned (Surprenant, A., F. Rassendren, E. Kawashima, R.A. North and G. Buell. 1996. Science (Wash. DC). 272:735–737) cytolytic receptor is unknown. In vitro and in vivo activation of the macrophage and microglial cell P2Z/P2X7 receptor by exogenous ATP causes a large and rapid release of mature IL-1β. In the present report we investigated the role of microglial P2Z/P2X7 receptor in IL-1β release triggered by LPS. Our data suggest that LPS-dependent IL-1β release involves activation of this purinergic receptor as it is inhibited by the selective P2Z/P2X7 blocker oxidized ATP and modulated by ATP-hydrolyzing enzymes such as apyrase or hexokinase. Furthermore, microglial cells release ATP when stimulated with LPS. LPS-dependent release of ATP is also observed in monocyte-derived human macrophages. It is suggested that bacterial endotoxin activates an autocrine/paracrine loop that drives ATP-dependent IL-1β secretion.
Stochastic Strong Ground Motion Simulation of the Southern Aegean Sea Benioff Zone Intermediate‐Depth EarthquakesStochastic Strong Ground Motion Simulation of the Southern Aegean Sea Intermediate‐Depth Earthquakes

We employ the stochastic finite-fault modeling approach of Motazedian and Atkinson (2005), as adapted by Boore (2009), for the simulation of Fourier amplitude spectra (FAS) of intermediate-depth earthquakes in the southern Aegean Sea subduction (southern Greece). To calibrate the necessary model parameters of the stochastic finite-fault method, we used waveform data from both acceleration and broadband-velocity sensor instruments for intermediate-depth earthquakes (depths ∼45–140 km) with M 4.5–6.7 that occurred along the southern Aegean Sea Wadati–Benioff zone. The anelastic attenuation parameters employed for the simulations were adapted from recent studies, suggesting large back-arc to fore-arc attenuation differences. High-frequency spectral slopes (kappa values) were constrained from the analysis of a large number of earthquakes from the high-density EGELADOS (Exploring the Geodynamics of Subducted Lithosphere Using an Amphibian Deployment of Seismographs) temporary network. Because of the lack of site-specific information, generic site amplification functions available for the Aegean Sea region were adopted. Using the previous source, path, and site-effect constraints, we solved for the stressparameter values by a trial-and-error approach, in an attempt to fit the FAS of the available intermediate-depth earthquake waveforms. Despite the fact that most source, path, and site model parameters are based on independent studies and a single source parameter (stress parameter) is optimized, an excellent comparison between observations and simulations is found for both peak ground acceleration (PGA) and peak ground velocity (PGV), as well as for FAS values. The final stress-parameter values increase with moment magnitude, reaching large values (> 300 bars) for events M ≥ 6:0. Blind tests for an event not used for the model calibration verify the good agreement of the simulated and observed ground motions for both back-arc and alongarc stations. The results suggest that the employed approach can be efficiently used for the modeling of large historical intermediate-depth earthquakes, as well as for seismic hazard assessment for similar intermediate-depth events in the southern Aegean Sea area. Electronic Supplement: Input parameter file for program EXSIM_DMB and tables of site amplification factors.