Miracle-dz/UniFAR-FTUs huggingface dataset:
Structure of the Nucleotide Complex of PyrR, the pyr Attenuation Protein from Bacillus caldolyticus, Suggests Dual Regulation by Pyrimidine and Purine Nucleotides

ABSTRACT PyrR is a protein that regulates the expression of genes and operons of pyrimidine nucleotide biosynthesis (pyr genes) in many bacteria. PyrR acts by binding to specific sequences on pyr mRNA and causing transcriptional attenuation when intracellular levels of uridine nucleotides are elevated. PyrR from Bacillus subtilis has been purified and extensively studied. In this work, we describe the purification to homogeneity and characterization of recombinant PyrR from the thermophile Bacillus caldolyticus and the crystal structures of unliganded PyrR and a PyrR-nucleotide complex. The B. caldolyticus pyrR gene was previously shown to restore normal regulation of the B. subtilis pyr operon in a pyrR deletion mutant. Like B. subtilis PyrR, B. caldolyticus PyrR catalyzes the uracil phosphoribosyltransferase reaction but with maximal activity at 60°C. Crystal structures of B. caldolyticus PyrR reveal a dimer similar to the B. subtilis PyrR dimer and, for the first time, binding sites for nucleotides. UMP and GMP, accompanied by Mg2+, bind specifically to PyrR active sites. Nucleotide binding to PyrR is similar to other phosphoribosyltransferases, but Mg2+ binding differs. GMP binding was unexpected. The protein bound specific sequences of pyr RNA 100 to 1,000 times more tightly than B. subtilis PyrR, depending on the RNA tested and the assay method; uridine nucleotides enhanced RNA binding, but guanosine nucleotides antagonized it. The new findings of specific GMP binding and its antagonism of RNA binding suggest cross-regulation of the pyr operon by purines.
Modeling Gap Seeking Behaviors for Agent-based Crowd Simulation

Research on agent-based crowd simulation has gained tremendous momentum in recent years due to the increase of computing power. One key issue in this research area is to develop various behavioral models to capture the microscopic behaviors of individuals (i.e., agents) in a crowd. In this paper, we propose a novel behavior model for modeling the gap seeking behavior which can be frequently observed in real world scenarios where an individual in a crowd proactively seek for gaps in the crowd flow so as to minimize potential collision with other people. We propose a two-level modeling framework and introduce a gap seeking behavior model as a proactive conflict minimization maneuver at global navigation level. The model is integrated with the reactive collision avoidance model at local steering level. We evaluate our model by simulating a real world scenario. The results show that our model can generate more realistic crowd behaviors compared to the classical social-force model in the given scenario.
MammaPrint versus EndoPredict: Poor correlation in disease recurrence risk classification of hormone receptor positive breast cancer

Introduction Correct risk assessment of disease recurrence in patients with early breast cancer is critically important to detect patients who may be spared adjuvant chemotherapy. In clinical practice this is increasingly done based on the results of gene expression assays. In the present study we compared the concordance of the 70-gene signature MammaPrint (MP) with the 12 gene assay EndoPredict (EP). Methods Representative tissue of 48 primary tumours was analysed with the MP during routine diagnostic purposes. Corresponding formalin-fixed, paraffin-embedded tissue was thereafter analysed by the EP test. Risk categories of both tests were compared. Results 41 of 48 tumours could be directly compared by both tests. Of the 17 MP low risk cases, only 9 were considered low risk by EP (53% agreement) and of the 24 MP high risk cases, 18 were high risk by EP (75% agreement). Discrepancies occurred in 14 of 41 cases (34.1%). There was only a weak and non-significant correlation between the MP and EP test with an overall concordance of only 66%. The original therapeutic recommendation was based on the MP and would have been changed in 38% of the patients following EP test results. 4 patients developed distant metastases. The respective tumours of these patients were all classified as high risk by the EP, but only 3 were classified as high risk by the MP. Conclusion Both tests resulted in different treatment recommendations for a significant proportion of patients and cannot be used interchangeably. The results underscore the urgent need for further comparative analyses of multi-genomic tests to avoid misclassification of disease recurrence risk in breast cancer patients.
Wisconsinan stratigraphy at northern margin of Strait of Georgia, southern Cortes Island and vicinity, British Columbia

About 130 m of Wisconsinan strata, exposed on the northern margin of the Strait of Georgia record climate-controlled, cyclical, predominantly marine deposition. Position below sea level of the base of the sediments (>80 m in a well) is attributed to pre-Wisconsinan glacial erosion within the strait. The early Wisconsinan Semiahmoo Glaciation produced advance deposits (Cortes Sand, new formation) and glaciomarine sediments and till (Marina Island Diamict, new). The middle Wisconsinan Olympia Nonglacial Interval is represented by the upper member of the Cowichan Head Formation, which unconformably overlies the diamict. The late Wisconsinan Fraser Glaciation generated advance deposits (Quadra Sand); glaciomarine sediments (Mansons Landing Diamict, new); inferred till and glaciomarine sediments represented by boulder lag only; subaqueous delta sediments; and again inferred glaciomarine sediments, winnowed to boulder lag during the isostasy-driven final emergence. Page 1 Résumé : La rive septentrionale du détroit de Georgia recèle des strates wisonsiniennes d’une épaisseur de 130 m qui témoignent d’une sédimentation cyclique, sujette aux variations climatiques et ayant eu lieu surtout en milieu marin. La base de la section est située sous le niveau de la mer (à plus de 80 m de profondeur dans un puits), ce que l’on attribue à une érosion glaciaire pré-wisconsinienne dans le détroit. La Glaciation de Semiahmoo du Wisconsin inférieur est à l’origine de dépôts d’avancée (une nouvelle formation, le Sable de Cortes) ainsi que de sédiments glaciomarins et de tills (une nouvelle unité, le Diamicton de Marina Island). L’intervalle non glaciaire d’Olympia du Wisconsin moyen est représenté par le membre supérieur de la Formation de Cowichan Head, qui repose en discordance sur le diamicton. La Glaciation de Fraser du Wisconsin supérieur a produit des dépôts d’avancée (le Sable de Quadra); des sédiments glaciomarins (le Diamicton de Mansons Landing, nouvelle unité); ce que l’on suppose être du till et des sédiments glaciomarins représentés uniquement par un résidu de blocs; des sédiments de delta subaquatique; et, enfin, ce que l’on croit être des sediments glaciomarins qui ont été vannés pour former un résidu de blocs pendant la phase finale d’émersion isostasique.
Antioxidant and Protective Effects of Bupleurum falcatum on the L-Thyroxine-Induced Hyperthyroidism in Rats

Bupleuri Radix (BR), the dried roots of Bupleurum falcatum L. , has been used in folk medicine as an antiinflammatory and antioxidative agent. The aqueous extract of BR was evaluated for its possible ameliorative effect in the regulation of hyperthyroidism in l-thyroxine- (LT4-) induced rat model. After oral administration of 300, 150, and 75 mg/kg of BR extracts, once a day for 15 days from 12th LT4 treatments, changes on the body, thyroid gland, liver, and epididymal fat pad weights, serum triiodothyronine, thyroxine, thyroid-stimulating hormone, asparte aminotransferase and alanine aminotransferase concentrations, hepatic lipid peroxidation, glutathione contents, superoxide dismutase, and catalase activities were investigated with thyroid gland, liver, and epididymal fat histopathological changes. The effects of BR extracts were compared with that of propylthiouracil, a standard antithyroid drug 10 mg/kg (intraperitoneally). In this experiment, BR extracts dose dependently reversed LT4-induced hyperthyroidisms, and these effects indicating their potential in the regulation of hyperthyroidism. Further, the BR extract normalized LT4-induced liver oxidative stresses, and also reduced liver and epididymal fat pad changes. BR extracts 150 mg/kg showed comparable effects on the LT4-induced rat hyperthyroidism as compared with PTU 10 mg/kg. These effects of BR may help the improvement of hyperthyroidisms and accompanied various organ damages.
Therapeutical approach to plasma homocysteine and cardiovascular risk reduction

Homocysteine is a sulfur-containing aminoacid produced during metabolism of methionine. Since 1969 the relationship between altered homocysteine metabolism and both coronary and peripheral atherotrombosis is known; in recent years experimental evidences have shown that elevated plasma levels of homocysteine are associated with an increased risk of atherosclerosis and cardiovascular ischemic events. Several mechanisms by which elevated homocysteine impairs vascular function have been proposed, including impairment of endothelial function, production of reactive oxygen species (ROS) and consequent oxidation of low-density lipids. Endothelial function is altered in subjects with hyperhomocysteinemia, and endothelial dysfunction is correlated with plasma levels of homocysteine. Folic acid and B vitamins, required for remethylation of homocysteine to methionine, are the most important dietary determinants of homocysteine and daily supplementation typically lowers plasma homocysteine levels; it is still unclear whether the decreased plasma levels of homocysteine through diet or drugs may be paralleled by a reduction in cardiovascular risk.
Differentiation of the cardiac outflow tract components in alevins of the sturgeon Acipenser naccarii (Osteichthyes, Acipenseriformes): Implications for heart evolution

Previous work showed that in the adult sturgeon an intrapericardial, nonmyocardial segment is interposed between the conus arteriosus of the heart and the ventral aorta. The present report illustrates the ontogeny of this intermediate segment in Acipenser naccarii. The sample studied consisted of 178 alevins between 1 and 24 days posthatching. They were examined using light and electron microscopy. Our observations indicate that the entire cardiac outflow tract displays a myocardial character during early development. Between the fourth and sixth days posthatching, the distal portion of the cardiac outflow tract undergoes a phenotypical transition, from a myocardial to a smooth muscle‐like phenotype. The length of this region with regard to the whole outflow tract increases only moderately during subsequent developmental stages, becoming more and more cellularized. The cells soon organize into a pattern that resembles that of the arterial wall. Elastin appears at this site by the seventh day posthatching. Therefore, two distinct components, proximal and distal, can be recognized from the fourth day posthatching in the cardiac outflow tract of A. naccarii. The proximal component is the conus arteriosus, characterized by its myocardial nature and the presence of endocardial cushions. The distal component transforms into the intrapericardial, nonmyocardial segment mentioned above, which is unequivocally of cardiac origin. We propose to designate this segment the “bulbus arteriosus” because it is morphogenetically equivalent to the bulbus arteriosus of teleosts. The present findings, together with data from the literature, point to the possibility that cells from the cardiac neural crest are involved in the phenotypical transition that takes place at the distal portion of the cardiac outflow tract, resulting in the appearance of the bulbus arteriosus. Moreover, they suggest that the cardiac outflow tract came to be formed by a bulbus arteriosus and a conus arteriosus from an early period of the vertebrate evolutionary story. Finally, we hypothesize that the embryonic truncus of birds and mammals is homologous to the bulbus arteriosus of fish. J. Morphol. 260:172–183, 2004. © 2004 Wiley–Liss, Inc.
Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors

Oncocytic tumors are a distinctive class of proliferative lesions composed of cells with a striking degree of mitochondrial hyperplasia that are particularly frequent in the thyroid gland. To understand whether specific mitochondrial DNA (mtDNA) mutations are associated with the accumulation of mitochondria, we sequenced the entire mtDNA in 50 oncocytic lesions (45 thyroid tumors of epithelial cell derivation and 5 mitochondrion-rich breast tumors) and 52 control cases (21 nononcocytic thyroid tumors, 15 breast carcinomas, and 16 gliomas) by using recently developed technology that allows specific and reliable amplification of the whole mtDNA with quick mutation scanning. Thirteen oncocytic lesions (26%) presented disruptive mutations (nonsense or frameshift), whereas only two samples (3.8%) presented such mutations in the nononcocytic control group. In one case with multiple thyroid nodules analyzed separately, a disruptive mutation was found in the only nodule with oncocytic features. In one of the five mitochondrion-rich breast tumors, a disruptive mutation was identified. All disruptive mutations were found in complex I subunit genes, and the association between these mutations and the oncocytic phenotype was statistically significant (P = 0.001). To study the pathogenicity of these mitochondrial mutations, primary cultures from oncocytic tumors and corresponding normal tissues were established. Electron microscopy and biochemical and molecular analyses showed that primary cultures derived from tumors bearing disruptive mutations failed to maintain the mutations and the oncocytic phenotype. We conclude that disruptive mutations in complex I subunits are markers of thyroid oncocytic tumors.
Crustal properties in the transition from orogenic to cratonic areas from seismological analysis: example of the Baltic shield and the Scandinavian Mountains

The mechanism of support for the present topography of Scandinavia is not well explained by current crustal models. High topography in Norway and Sweden (Scandinavian Alps) is directly in contact with a relatively flat region (the Baltic shield). A crustal root beneath the Scandinavian Alps, expected from Airy isostatic calculations, is not present and the gravity anomaly map suggests lateral variations in density support present day topography. To bring new constrains on the variation of crustal properties we use P-receiver functions and ambient seismic noise. Using these methods we quantify Moho depth and depth-velocity variations across the crust. P-receiver functions indicate the presence of a high velocity layer at the base of the crust, interpreted as magmatic underplating or eclogitization. Ambient seismic noise provides data from Rayleigh wave seismic tomography and identifies the presence of a low velocity layer associated with granite intrusion in the upper-middle crust. Our new crustal thickness map shows that the topography at the surface is not reflected by the Moho topography in this region. We observe a relative thickening of the crust from the Atlantic coast (40 km) to the Gulf of Bothnia (44 km). Secondly, Moho sharpness analysis and 1D depth-velocity profiles show a difference in the transition from crust and upper mantle. A high velocity layer (Vp>7.1 km.s−1) beneath the Baltic shield is missing beneath the Scandinavian mountains. This observation explains the crustal thickness variations beneath the mountain belt and the shield, with magmatic underplating beneath the shield and a delamination of the lower crust due to eclogitization process beneath the mountain range. In addition the presence of a local low density layer (granitic body) in the upper crust beneath the northern mountains seems to be a possible mechanism to explain the presence day topography in this region. ”A theory is a supposition which we hope to be true, a hypothesis is a supposition which we expect to be useful; fictions belong to the realm of art; if made to intrude elsewhere, they become either make-believes or mistakes. ” George Johnstone Stoney (1826-1911)
Xeroderma Pigmentosum Group A Suppresses Mutagenesis Caused by Clustered Oxidative DNA Adducts in the Human Genome

Clustered DNA damage is defined as multiple sites of DNA damage within one or two helical turns of the duplex DNA. This complex damage is often formed by exposure of the genome to ionizing radiation and is difficult to repair. The mutagenic potential and repair mechanisms of clustered DNA damage in human cells remain to be elucidated. In this study, we investigated the involvement of nucleotide excision repair (NER) in clustered oxidative DNA adducts. To identify the in vivo protective roles of NER, we established a human cell line lacking the NER gene xeroderma pigmentosum group A (XPA). XPA knockout (KO) cells were generated from TSCER122 cells derived from the human lymphoblastoid TK6 cell line. To analyze the mutagenic events in DNA adducts in vivo, we previously employed a system of tracing DNA adducts in the targeted mutagenesis (TATAM), in which DNA adducts were site-specifically introduced into intron 4 of thymidine kinase genes. Using the TATAM system, one or two tandem 7,8-dihydro-8-oxoguanine (8-oxoG) adducts were introduced into the genomes of TSCER122 or XPA KO cells. In XPA KO cells, the proportion of mutants induced by a single 8-oxoG (7.6%) was comparable with that in TSCER122 cells (8.1%). In contrast, the lack of XPA significantly enhanced the mutant proportion of tandem 8-oxoG in the transcribed strand (12%) compared with that in TSCER122 cells (7.4%) but not in the non-transcribed strand (12% and 11% in XPA KO and TSCER122 cells, respectively). By sequencing the tandem 8-oxoG-integrated loci in the transcribed strand, we found that the proportion of tandem mutations was markedly increased in XPA KO cells. These results indicate that NER is involved in repairing clustered DNA adducts in the transcribed strand in vivo.
Novel Protein Kinases Ark1p and Prk1p Associate with and Regulate the Cortical Actin Cytoskeleton in Budding Yeast

Ark1p (actin regulating kinase 1) was identified as a yeast protein that binds to Sla2p, an evolutionarily conserved cortical actin cytoskeleton protein. Ark1p and a second yeast protein, Prk1p, contain NH2-terminal kinase domains that are 70% identical. Together with six other putative kinases from a number of organisms, these proteins define a new protein kinase family that we have named the Ark family. Lack of both Ark1p and Prk1p resulted in the formation of large cytoplasmic actin clumps and severe defects in cell growth. These defects were rescued by wild-type, but not by kinase-dead versions of the proteins. Elevated levels of either Ark1p or Prk1p caused a number of actin and cell morphological defects that were not observed when the kinase-dead versions were overexpressed instead. Ark1p and Prk1p were shown to localize to actin cortical patches, making these two kinases the first signaling proteins demonstrated to be patch components. These results suggest that Ark1p and Prk1p may be downstream effectors of signaling pathways that control actin patch organization and function. Furthermore, results of double-mutant analyses suggest that Ark1p and Prk1p function in overlapping but distinct pathways that regulate the cortical actin cytoskeleton.
Ozone Concentrations: A Robust Analysis of Multivariate Extremes

Data on ozone concentrations at four monitoring sites in central Canada are examined. Univariate extreme value methods do not allow for the required inference, and multivariate methods exploiting the joint dependence of the data are necessary. Families of multivariate extreme-value copulas with a flexible dependence structure and closed-form cumulative distribution functions have recently been derived. This article shows that maximum likelihood estimates of these parametric models may be obtained numerically and that their use can lead to increased efficiency in the estimation of margins. We do not, however, have any assurance that all data are well modeled by these distributions, because the space of multivariate extreme-value copulas is infinite-dimensional, and data on ozone levels are prone to outliers. This article addresses the robust methods required for proper analysis.
Colonic ulcers accompanying collagenous colitis: implication of nonsteroidal anti-inflammatory drugs

OBJECTIVES:A small minority of otherwise typical collagenous colitis (CC) patients also have mucosal ulceration (CC-U). We studied the association of CC-U cases with ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) as a possible explanation for the mucosal ulceration.METHODS:Clinical information and histological features were reviewed in nine cases of biopsy-diagnosed CC-U. Biopsies from 18 unselected cases of CC without ulceration were reviewed for comparison.RESULTS:Of nine patients with CC-U, seven (77.8%) had a history of NSAID ingestion, compared with four of 18 CC controls (20.2%) (p = 0.006). The diarrhea resolved after cessation of NSAID use in four CC-U patients, partially resolved in one patient, and persisted in one patient. The outcome was not available in one patient. Of the two CC-U patients who did not use NSAIDs, one patient was taking lisinopril (angiotensin-converting enzyme inhibitor), and the diarrhea resolved after stopping the drug; the ulceration in the second patient was thought to be ischemic in origin.CONCLUSION:Collagenous colitis with ulceration has a strong association with NSAID ingestion. Evaluation of medications and cessation of NSAIDs should be considered as a therapeutic option in cases of collagenous colitis with colonic ulceration.
Disturbances of sleep continuity in women during the menopausal transition.

OBJECTIVES The objective of the study was to evaluate the prevalence of sleep continuity disorders in women during menopausal transition, to evaluate the relationship between disturbances of sleep continuity and the severity of menopausal syndrome and the occurrence of various symptoms of this syndrome, as well as to evaluate the association between the presence of sleep disturbances and serum concentrations of gonadotropins, prolactin and sex hormones. METHODS Consecutive 140 women (mean age 54.4 ± 4.7 years) searching for the treatment in the Clinic for Gynaecological Endocrinology who reported symptoms of menopausal syndrome were investigated. The type and severity of disturbances of sleep continuity were evaluated using a survey based on the sleep related questions from Hamilton Depression Rating Scale. The severity of symptoms of menopausal syndrome was assessed using the Kupperman Index. The concentration of the following hormones in blood serum was tested: FSH, LH, 17β-estradiol, PRL, total testosterone, DHEAS and SHBG. RESULTS Disturbances of sleep continuity were a prevalent complaint in the studied group of women. Difficulties in falling asleep were found in 57.8% of women, difficulties in maintaining sleep in 70%, waking up too early in 60.7%. The severity of all three types of sleep continuity disturbances was related to the severity of menopausal syndrome as measured with Kupperman Index (Spearman correlation coefficient r = 0.63, r = 0.61, r = 0.52, respectively; p < 0.001). Difficulties in maintaining sleep were negatively correlated with the concentration of FSH (r = - 0.19; p < 0.05), 17β-estradiol (r = - 0.19; p < 0.05) and SHBG (r = - 0.18; p < 0.05), difficulties in falling asleep negatively correlated with the concentration of 17β-estradiol in the blood serum (r = - 0.19; p < 0.05). CONCLUSIONS Sleep continuity disturbances are frequently reported by women during the menopausal transition. Interventions aimed at reducing the symptoms of menopausal syndrome should be considered as important action to improve sleep quality in this population of patients.