Miracle-dz/UniFAR-FTUs huggingface dataset:
Analysis of K-ras, APC, and beta-catenin in aberrant crypt foci in sporadic adenoma, cancer, and familial adenomatous polyposis.

BACKGROUND & AIMS We have previously shown that aberrant crypt foci (ACF) are the putative precursor lesions of colorectal adenomas and subsequent cancer in humans using magnifying endoscopy. The present study was designed to investigate these genetic alterations in ACF biopsy specimens from normal subjects, familial adenomatous polyposis (FAP) or sporadic patients. METHODS The non-FAP cases included 34 normal subjects, 35 colorectal adenoma patients, and 19 colorectal cancer patients; there were 4 FAP patients. Biopsies were performed on ACF by magnifying endoscopy. K-ras mutations were analyzed by 2-step polymerase chain reaction and restriction fragment length polymorphism, APC mutations by in vitro-synthesized protein assay, and beta-catenin mutations by direct sequencing. Full-length APC and beta-catenin were detected by immunofluorescence. RESULTS In non-FAP cases, K-ras mutations were detected in 82% (89/106) of nondysplastic ACF and 63% (17/27) of dysplastic ACF. APC mutation and beta-catenin accumulation were not detected in non-FAP ACF, whereas in adenoma of these patients, positivity of APC mutation and beta-catenin accumulation were 78% (24/31), and that of K-ras mutation was 65% (20/31). FAP patients showed K-ras mutations in only 13% (1/8) of dysplastic ACF, which is the predominant form of ACF found in FAP. In FAP patients, somatic APC mutations were found in 100% of dysplastic ACF, as they are in adenoma. The frequency of K-ras mutations was 73% (8 of 11) in FAP adenoma. CONCLUSIONS The data suggest that in sporadic colorectal carcinogenesis, assuming the biological implication of ACF as a precursor of adenomas, there is a route where K-ras mutation mainly occurs during the formation of ACF, which then become adenomas wherein APC mutation occurs. In FAP, however, somatic mutation of APC predominantly occurs during ACF formation, followed by K-ras mutation.
Origins of specificity and cross‐talk in metal ion sensing by Bacillus subtilis Fur

Fur (ferric uptake regulator) is the master regulator of iron homeostasis in many bacteria, but how it responds specifically to Fe(II) in vivo is not clear. Biochemical analyses of Bacillus subtilis Fur (BsFur) reveal that in addition to Fe(II), both Zn(II) and Mn(II) allosterically activate BsFur–DNA binding. Dimeric BsFur co‐purifies with site 1 structural Zn(II) (Fur2Zn2) and can bind four additional Zn(II) or Mn(II) ions per dimer. Metal ion binding at previously described site 3 occurs with highest affinity, but the Fur2Zn2:Me2 form has only a modest increase in DNA binding affinity (approximately sevenfold). Metallation of site 2 (Fur2Zn2:Me4) leads to a ∼ 150‐fold further enhancement in DNA binding affinity. Fe(II) binding studies indicate that BsFur buffers the intracellular Fe(II) concentration at ∼ 1 μM. Both Mn(II) and Zn(II) are normally buffered at levels insufficient for metallation of BsFur site 2, thereby accounting for the lack of cross‐talk observed in vivo. However, in a perR mutant, where the BsFur concentration is elevated, BsFur may now use Mn(II) as a co‐repressor and inappropriately repress iron uptake. Since PerR repression of fur is enhanced by Mn(II), and antagonized by Fe(II), PerR may co‐regulate Fe(II) homeostasis by modulating BsFur levels in response to the Mn(II)/Fe(II) ratio.
Prevalence of Type III Secretion Protein Exoenzymes and Antimicrobial Susceptibility Patterns from Bloodstream Isolates of Patients with Pseudomonas aeruginosa Bacteremia

Abstract The purpose of this study was to determine the prevalence of two type III secretion effector proteins, exoU and exoS from bloodstream isolates of hospitalized patients with Pseudomonas aeruginosa (PSA) bacteremia, to characterize antimicrobial susceptibility patterns, and to compare mortality rates. PSA bloodstream isolates and antibiotic susceptibility profiles were collected from a university-affiliated hospital. exoS and exoU genes were detected by polymerase chain reaction. Hospital mortality was assessed by medical chart review. 119 of 122 (97.5%) PSA bloodstream isolates contained either the exoS or exoU genes. exoS was the most prevalent (n=86; 70.5%) followed by exoU (n=31; 25.4%), both genes (n=2; 1.6%) or neither gene (n=3; 2.5%). Isolates containing the exoU gene were significantly more likely to be resistant to cefepime, ceftazidime, piperacillintazobactam, carbapenems, fluoroquinolones, and gentamicin (p<0.05 for all). Mortality was high in patients with PSA bacteremia and did not differ among patients infected with the exoS isolates (n=37; 43%) or exoU isolates (n=11; 35%). One of two type III secretion effector proteins were almost universally present in PSA bloodstream isolates. Isolates containing the exoU gene were more likely to be resistant to multiple antibiotics.
EphB1-mediated Cell Migration Requires the Phosphorylation of Paxillin at Tyr-31/Tyr-118*

Interactions between Eph receptors and their membrane-bound ligands (ephrins) are of critical importance for key developmental processes such as boundary formation or vascular development. Their downstream signaling pathways are intricate and heterogeneous at several levels, the combined effect being a highly complex and flexible system. Here we demonstrate that activated EphB1 induces tyrosine phosphorylation of the focal adhesion protein paxillin at Tyr-31 and Tyr-118 and is recruited to paxillin-focal adhesion kinase (FAK) complexes. Pretreatment with the specific Src inhibitor PP2, or expression of dominant-negative, kinase-dead c-Src abrogates EphB1-induced tyrosine phosphorylation of paxillin. Cells transfected with the paxillin mutant Y31F/Y118F displayed a reduced migration in response to ephrin B2 stimulation. Furthermore, expression of an LD4 deletion mutant (paxillin ΔLD4) significantly reduces EphB1-paxillin association, paxillin tyrosine phosphorylation, as well as EphB1-dependent cell migration. Finally, mutation of the Nck-binding site of EphB1 (Y594F) interrupts the interaction between Nck, paxillin, and EphB1. These data suggest a model in which ligand-activated EphB1 forms a signaling complex with Nck, paxillin, and focal adhesion kinase and induces tyrosine phosphorylation of paxillin in a c-Src-dependent manner to promote cell migration.
Blocked and Alternating Variable Practice and Unintended Spatial Variations in Continuous Aiming Movements

The main goal of the study was to test a prediction of schema theory: a wider range of variable practice would result in better transfer performance compared to a narrower range of variable practice in less-studied, continuous aiming movements. Constant and variable amplitude continuous aiming movements were investigated in the preferred hand of participants of college age (N = 32; 8 men, 24 women). Participants made continuous rapid reversal movements with a lever in the horizontal plane. Groups attempted to reach a short (20°) target and a long target (either 45° or 70°) in separate constant-practice conditions, but alternated between the two targets in a variable practice condition. On the transfer test, participants alternated between unpracticed 10° and 80° targets. Four blocks of practice trials were provided in each condition, with 20 movements made in each. Movements were more accurate and consistent during constant practice compared to variable practice, with the 20°-70° group having greater spatial errors compared to the 20°-45° group. Both groups performed equally well on the novel transfer test suggesting that adequate practice variability had been provided during acquisition.
Interaction of lp-dlg/KIAA0583, a Membrane-associated Guanylate Kinase Family Protein, with Vinexin and β-Catenin at Sites of Cell-Cell Contact*

Vinexin is a recently identified cytoskeletal protein and plays a key role in the regulation of cytoskeletal organization and signal transduction. Vinexin localizes at sites of cell-extracellular matrix adhesion in NIH3T3 fibroblasts and at sites of cell-cell contact in epithelial LLC-PK1 cells. Expression of vinexin promotes the formation of actin stress fiber, but the role of vinexin at sites of cell-cell contact is unclear. Here we identified lp-dlg/KIAA0583 as a novel binding partner for vinexin by using yeast two-hybrid screening. lp-dlg/KIAA0583 has a NH2-terminal coiled-coil-like domain, in addition to four PDZ domains, an Src homology (SH) 3 domain, and a guanylate kinase domain, which are conserved structures in membrane-associated guanylate kinase family proteins. The third SH3 domain of vinexin bound to the region between the second and third PDZ domain of lp-dlg, which contains a proline-rich sequence. lp-dlg colocalized with vinexin at sites of cell-cell contact in LLC-PK1 cells. Furthermore, lp-dlg colocalized with β-catenin, a major adherens junction protein, in LLC-PK1 cells. Co-immunoprecipitation experiments revealed that both endogenous and epitope-tagged deletion mutants of lp-dlg/KIAA0583 associated with β-catenin. We also showed that these three proteins could form a ternary complex. Together these findings suggest that lp-dlg/KIAA0583 is a novel scaffolding protein that can link the vinexin-vinculin complex and β-catenin at sites of cell-cell contact.
Substrate Specificity of Human Endonuclease III (hNTH1)

Base excision repair of oxidized pyrimidines in human DNA is initiated by the DNAN-glycosylase/apurinic/apyrimidinic (AP) lyase, human NTH1 (hNTH1), the homolog of Escherichia coliendonuclease III (Nth). In contrast to Nth, the DNAN-glycosylase activity of hNTH1 is 7-fold greater than its AP lyase activity when the DNA substrate contains a thymine glycol (Tg) opposite adenine (Tg:A) (Marenstein, D. R., Ocampo, M. T. A., Chan, M. K., Altamirano, A., Basu, A. K., Boorstein, R. J., Cunningham, R. P., and Teebor, G. W. (2001) J. Biol. Chem. 276, 21242–21249). When Tg is opposite guanine (Tg:G), the two activities are of the same specific activity as the AP lyase activity of hNTH1 against Tg:A (Ocampo, M. T. A., Chaung, W., Marenstein, D. R., Chan, M. K., Altamirano, A., Basu, A. K., Boorstein, R. J., Cunningham, R. P., and Teebor, G. W. (2002) Mol. Cell. Biol. 22, 6111–6121). We demonstrate here that hNTH1 was inhibited by the product of its DNA N-glycosylase activity directed against Tg:G, the AP:G site. In contrast, hNTH1 was not as inhibited by the AP:A site arising from release of Tg from Tg:A. Addition of human APE1 (AP endonuclease-1) increased dissociation of hNTH1 from the DNA N-glycosylase-generated AP:A site, resulting in abrogation of AP lyase activity and an increase in turnover of the DNA N-glycosylase activity of hNTH1. Addition of APE1 did not abrogate hNTH1 AP lyase activity against Tg:G. The stimulatory protein YB-1 (Marenstein et al.), added to APE1, resulted in an additive increase in both activities of hNTH1 regardless of base pairing. Tg:A is formed by oxidative attack on thymine opposite adenine. Tg:G is formed by oxidative attack on 5-methylcytosine opposite guanine (Zuo, S., Boorstein, R. J., and Teebor, G. W. (1995) Nucleic Acids Res. 23, 3239–3243). It is possible that the in vitro substrate selectivity of mammalian NTH1 and the concomitant selective stimulation of activity by APE1 are indicative of selective repair of oxidative damage in different regions of the genome.
Competitive exclusion of uropathogens from human uroepithelial cells by Lactobacillus whole cells and cell wall fragments

Previous studies have shown that indigenous bacteria isolated from cervical, vaginal, and urethral surfaces of healthy women are able to adhere to human uroepithelial cells in vitro. Furthermore, these organisms were found to block the adherence of uropathogenic bacteria to uroepithelial cells from women with and without a history of urinary tract infections. In the present study, complete or partial inhibition of the adherence of gram-negative uropathogens was achieved by preincubating the uroepithelial cells with bacterial cell wall fragments isolated from a Lactobacillus strain. Competitive exclusion was most effective with whole viable cells and less effective with cell wall fragments obtained by sonication, extraction with sodium dodecyl sulfate, and treatment with sodium dodecyl sulfate and acid. Analysis of the Lactobacillus cell wall preparations suggested that lipoteichoic acid was responsible for the adherence of the Lactobacillus cells to uroepithelial cells but that steric hindrance was the major factor in preventing the adherence of uropathogens. This conclusion was also supported by blockage studies with reconstituted lipoteichoic acid-peptidoglycan, which was more effective at blocking adherence than lipoteichoic acid or peptidoglycan alone. The results suggest that the normal flora of the urinary tract may be used to protect against the attachment of uropathogens to the surfaces of uroepithelial cells. The long-term implications of these findings may lead to alternative methods for the management and prevention of recurrent urinary tract infections in females.
Activation of the reward system during sympathetic concern is mediated by two types of empathy in a familiarity-dependent manner

Humans work to improve the situation of others through sympathetic concern. The empathic joy hypothesis proposes that the urge to help is stimulated by enhanced sensitivity to vicarious joy achieved through helping a recipient to meet their needs. We further hypothesized that the positive feeling-related brain activation that occurs in the striatum during sympathetic concern is enhanced by empathy in a familiarity-dependent manner. To test this, we conducted behavioral and functional magnetic resonance imaging experiments in which two participants simultaneously played a virtual ball-toss game where either the subjects' partner or an unfamiliar player was isolated by the other players. The subjects showed sympathetic behavior by tossing the ball to the isolated player and reported enhancement of self-positive feelings and anticipation of feeling improvements of the isolated player during sympathetic behaviors. Activation in the bilateral dorsal striatum became more prominent during the behaviors, supporting the empathic joy hypothesis. Dorsal striatal activity when helping a romantic partner positively correlated with affective empathic traits toward that partner, whereas the activity measured when helping a stranger positively correlated with perspective-taking traits. The correlation results further revealed a familiarity-dependent empathic enhancement of positive feelings. Therefore, sympathetic concern is invoked through empathic positive feeling.
West Nile virus meningoencephalitis: MR imaging findings.

BACKGROUND AND PURPOSE Reports of MR imaging in West Nile virus (WNV) meningoencephalomyelitis are few and the described findings limited. The purpose of this study was to review the spectrum of MR imaging findings for WNV meningoencephalomyelitis and investigate whether any of the findings correlates with clinical presentation of flaccid paralysis. METHODS We reviewed the MR imaging findings of 17 patients with confirmed WNV encephalitis and/or myelitis. MR imaging brain studies were evaluated for location of signal intensity abnormalities, edema, hydrocephalus, or abnormal enhancement. MR imaging spine studies were evaluated for signal intensity abnormalities in cord and/or enhancement. RESULTS Retrospective review of the MR imaging studies of 17 patients was performed by 2 neuroradiologists. Eleven of 16 brain MR images demonstrated abnormalities. Eight (50%) patients had abnormal studies related to meningoencephalitis. All 8 patients had abnormal findings in the deep gray matter and/or brain stem; 2 had additional white matter abnormalities. Three patients with abnormal MR studies of the spine had extremity weakness on examination. The imaging findings included abnormal signal intensity more pronounced in the ventral horns and/or enhancement around the conus medullaris and cauda equina. One patient had additional abnormalities in the pons. CONCLUSION Abnormal MR imaging findings in patients with WNV meningoencephalomyelitis are nonspecific but not uncommon. Anatomic areas commonly affected are basal ganglia, thalami, mesial temporal structures, brain stem, and cerebellum. Extremity weakness or flaccid paralysis corresponds to spinal cord/cauda equina abnormalities.
Learning from MOOCs: lessons for the future

In addition to stimulating a valuable worldwide debate about online learning in HE (higher education), MOOCs (massive open online courses) have also triggered a large amount of very active educational and technological research. This research is helping to inform further developments in the design and delivery of MOOCs themselves, but, importantly, is also providing insights into learning in more traditional HE settings where the use of technology is now commonplace. In this chapter, I review some of the research approaches to studying MOOCs and some of the findings from this research where broad agreement exists. Then I look to future opportunities in research and also in how MOOCs, and open education more generally, might align with a vision for digital education in universities in the 21st Century.
A Question of Culture or Economics? Public Attitudes to the European Union in Britain

Previous research has suggested that attitudes towards the European Union (EU) are shaped by two sets of considerations—economic and cultural. Using data from the 2015 British Social Attitudes survey, this article assesses which matters more in shaping attitudes in Britain towards the EU as the country prepares to vote in a referendum on whether it should remain in or leave the European Union. It shows that while concern about the cultural consequences of EU membership is widespread, voters are inclined to think that membership is economically beneficial. This cultural concern underpins a widespread scepticism about Europe, but voters are only likely to want to leave the EU if they are also convinced of the economic case for doing so.
A study of the Missing Data Problem for Intergenerational Mobility using Simulations

Applied research on the association between parent and child lifetime income is relying on income data that covers only part of the life cycle which may lead to misleading estimates of the intergenerational elasticity (IGE). In this paper I study the bias of IGE estimates for different missing-data scenarios based on simulated income processes. Using an income process from the income dynamics and risks literature to generate two linked generations’ complete income histories, I use Monte Carlo methods to study the relationship between available data patterns and the bias of the IGE. I find that the traditional approach using the average of the typically available log income observations leads to IGE estimates that are around 40 percent too small. Moreover, I show that the attenuation bias is not reduced by averaging over many father income observations. Using just one income observation for each generation at the optimal age (as discussed in the paper) or using weighted instead of unweighted averages can reduce the bias. In addition, the rank-rank slope is found to be clearly less sensitive to missing data.
Scaled Group Consensus in Multiagent Systems With First/Second-Order Continuous Dynamics

We investigate scaled group consensus problems of multiagent systems with first/second-order linear continuous dynamics. For a complex network consisting of two subnetworks with different physical quantities or task distributions, it is concerned with this case that the agents’ states in one subnetwork converge to a consistent value asymptotically, while the states in the other subnetwork approach another value with a ratio of the former. For the case of the information exchange being directed, novel consensus protocols are designed for both first-order and second-order dynamics to solve the scaled group consensus problems. By utilizing algebra theory, graph theory, and Lyapunov stability theory, several necessary and sufficient conditions are established to guarantee the agents’ states reaching the scaled group consensus asymptotically. Finally, several simulation results are presented to demonstrate the effectiveness of the theoretical results.
Biomaterials for bone regeneration.

OBJECTIVE This article reviews the literature on biomaterials used for bone regeneration. MATERIAL AND METHOD A total of seventeen bibliographic sources were found using the MEDLINE database and to avoid the variability of the search terms the thesaurus Mesh was used. RESULTS These materials act essentially due to their osteoconductive ability, although their osteoinductive capacity is being improved with the use of growth factors. As to their effectiveness, many differences exist between them and some even affect bone regeneration negatively. CONCLUSIONS Biomaterials used for bone regeneration are valid when the correct material is used. As yet the osteogenic capacity of autogenous bone has not been equalled by biomaterials. Tissue engineering has caused great interest because of its many possibilities, although more studies are necessary in order to achieve the ambitious expectations when it comes to tissue or organ regeneration in the human body.
The transition of workers from temporary to permanent employment: The Spanish case

Since fixed-term contracts were introduced in Spain, 98% of all new contracts have been of this type. Despite this massive flexibilisation of the labour market, Spanish unemployment still hits more than 20% of the labour force. To assess the effects of the introduction of fixed-term contracts on the labour market it is important to understand the dynamics of the conversion of temporary contracts into permanent ones. To address this issue we estimate a duration model for temporary employment, with competing risks of flowing into permanent employment versus non-employment, and flexible duration dependence. Preliminary results show that the probability of obtaining the renewal of a fixed-term contract on a permanent basis is not affected by the state of the business cycle. At the same time, the base-line hazard for renewals has a spike at three years of duration, coinciding with the legal limit of fixed-term contracts.
High-intensity laser-driven proton acceleration: influence of pulse contrast

Proton acceleration from the interaction of ultra-short laser pulses with thin foil targets at intensities greater than 1018 W cm−2 is discussed. An overview of the physical processes giving rise to the generation of protons with multi-MeV energies, in well defined beams with excellent spatial quality, is presented. Specifically, the discussion centres on the influence of laser pulse contrast on the spatial and energy distributions of accelerated proton beams. Results from an ongoing experimental investigation of proton acceleration using the 10 Hz multi-terawatt Ti : sapphire laser (35 fs, 35 TW) at the Lund Laser Centre are discussed. It is demonstrated that a window of amplified spontaneous emission (ASE) conditions exist, for which the direction of proton emission is sensitive to the ASE-pedestal preceding the peak of the laser pulse, and that by significantly improving the temporal contrast, using plasma mirrors, efficient proton acceleration is observed from target foils with thickness less than 50 nm.
Marginal Density Expansions for Diffusions and Stochastic Volatility I: Theoretical Foundations

Density expansions for hypoelliptic diffusions (X1,…,Xd) are revisited. We are particularly interested in density expansions of the projection ( XT1,⋯,XTl) at time T > 0 with l ≤ d. Global conditions are found that replace the well‐known “not‐in‐cut‐locus” condition known from heat kernel asymptotics. Our small‐noise expansion allows for a “second order” exponential factor. As an application, new light is shed on the Takanobu‐Watanabe expansion of Brownian motion and Lévy's stochastic area. Further applications include tail and implied volatility asymptotics in some stochastic volatility models, discussed in the companion paper . © 2013 Wiley Periodicals, Inc.